Toxicological appraisal of halogenated aromatic compounds following groundwater pollution: report on a WHO working group

copy Ac -o w*fo C Toxicological appraisal of "l *1. halogenated aromatic comPounds following groundwater pollution Report on a WHO Working CrouP REGIONAL OFFICE FOR EUROPE World Health Organization COPENHAGEN I 3 |4At 1960 ttsR H TOXICOLOGICAL APPRAISAL OF HALOGENATED AROMATIC COM POU N DS FOLLOWING GROUNDWATER POLLUTION Report on a WHO Working Group (@ WORLD HEALTH ORGANIZATION REGIONAL OFFICE FOR EUROPE COPEN}IAGEN 1980 ISBN 92 9020 196 7 O Wortd Health Organization 1980 Pubtications of the World Health Organization enjoy copyright pro- tection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. For rights of reproduction or translation, in part ot in toto, of publications issued by the WHO Regional Office for Europe application should be made to the Regional Office for Europe, Scherfigsvej 8, DK-2 100 Copenhagen @, Denmark. The Regional Office welcomes such applications. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of ar:y country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not men- tioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The views expressed in this publication are those of the participants in the Working Group and do not necessarily represent the decisions or the stated policy of the World Health Organization. PRINTED IN DENMARK Reissued under ISBN: 9789289024945 (print) in 2025. Originally published under ISBN-10: 9290201967. CONTENTS INTRODUCTION REVIEW OF INFORMATION Halogenated toluenes Major uses and environmental occurrence Physicochemical proPe rties Toxicological proPerties Exposure to contaminated water or air Halogenated benzenes and anilines Major uses Physicochemical proPerties Environmental occurrence Toxicological properties Chlorophenols.... Major uses Physicochemical proPe rties Environmental occurrence Toxicological properties HEALTH HAZARD: DATA ASSESSMENT .. Ilalogenated toluenes Halogenated benzenes Monochlorobenzene. o-Dictrlorobenzene. . p-Dictrlorobenzene. 1,2,4-Trichlorobenzene. . . . . Tetrachlorobenzene Hexactrlorobenzene (HCB) . . Chlorinated anilines Chlorophenols.... 2 $,5-Trichlorophenol 2,4,6-Tichlorophenol Pentachlorophenol. . Page CHATTER III J 3 3 6 6 ll ll ll t2 t3 t4 20 20 20 20 20 24 24 25 26 27 27 28 28 28 28 29 29 29 30 iii CHAPTER I. CHAPTER II. CHAPTER IV. PRACTICAL ASPECTS OF POLLUTION MONITORING AND CONTROL 3l 3l 32 Analyticaldetermination . . . . Watertreatment ... Methods of soil and groundwater pollution monitoring and control 33 35 35 36 CHAPTER V. CONCLUSIONS AND RECOMMENDATIONS. Groundwater pollution in Vicenza Province General . References 39 43 49 55 57 Annex l. Description of the groundwater pollution incident, Vicenza Province, Italy Annex 2. Methods of soil and groundwater pollution monitoring and control Annex 3. List of working papers Annex 4. List of participants . . tv IINTRODUCTION A Working group on criteria and guidelines for halogenated aromatic com- pounds was convened in Venice from 3 to 7 September 1979 by the WHO Regional Office for Europe and the Veneto Regional Government, under the auspices of the Italian Ministry of Health. It was attended by l3 experts from I I countries, l0 observers from Italy, a representative of the International Agency for Research on Cancer, and staff of WHO headquarters and the Re- gional Office for Europe. The immediate stimulus for holding the meeting was an episode of ground- water pollution in Vicenza Province, caused by process residues percolating from an effluent lagoon (see Annex I ). While the pollutants in this instance included a variety of o-halogenated chloro- and nitrotoluenes, the e pisode aroused interest in the possible adverse effects on health of a wider range of single-ring hal- ogenated aromatic compounds. The purpose of the meeting was thus to review available data on the chemistry, environmental occurrence and toxicology of halogenated toluenes, benzenes and phenols, to evaluate the possible health hazards associated with human exposure to them in the environment, and to recommend appropriate guidelines for health protection. The meeting was opened by Assessore F. Guidolin who, in welcoming the participants, stressed the importance of the meeting to the Veneto Regional Government. He noted that, given the dearth of information on halogenated aromatic compounds, there was a need to develop guidelines to solve and manage the practical problems involved in the use of such materials. These guidelines would be of value not only to the Veneto Region and to ltaly, but also to many other countries. Professor R. Vannugli, Director, Office of Intemational Relations, Min- istry of Health, Rome, recalled the long history of cooperation between the Italian Government and WHO and praised the initiative of the Veneto Re- gional Government in establishing links with the Regional Office and providing financial support for the meeting. Mr J.I. Waddington, Director, Promotion of Environmental Health, WHO Regional Office for Europe, referred to WHO activities related to toxic chemi- cals over the past 20 years and the recent development of the International Programme on Chemical Safety. The WHO regional offices were to take a leading role in implementing aspects of the Prografirme, such as manpower development, response to emergencies, and technical cooperation. The Re- gional Office for Europe was therefore actively developing an appropriate regional programme. The present meeting was important and timely and would I serve as a valuable prototype for tackling future problems of a similar nature elsewhere in the Region. He thanked the veneto Regional Government for sponsoring the meeting. Professor B. Paccagnella was elected Chairman of the meeting, Dr L. Rosi- val Vice-Chairman, and Dr S. Tarkowski Rapporteur. The group had to decide at the outset on a suitable approach to reviewing the large number of individual substances covered by the general description oi halogenated derivatives of benzene, phenol, and toluene (see Gambaretto, G. et al., Annex 3). As it was not considered feasible to study only the broad categories of substances, a number of important representative chemicals with- in each category were selected for detailed review. It was stressed that the enumerations should not be construed as priority lists. In making the selection, the meeting used criteria such as the estimated scale of worldwide production, industrial importance, known uses, and environ- mental occurrence. Scale of production was considered relevant in that processes are never totally efficient and therefore all generate different amounts of waste. The larger the scale of production, even for efficient processes, the greater the potential for release of waste to the environment. It should be noted, however, that the total global production of halogenated aromatics is very small compared to that of halogenated aliphatic compounds. The group recognized that the selection criteria would exclude from con- sideration those situations where specialized chemicals are produced in moder- ate amounts in perhaps only a few factories throughout the world. They might, nonetheless, cause local pollution problems. Given the impossibility oi all such situations being known internationally, they could be considered by an expert group such as the present one only when brought to its attention. It was for that reason that specific consideration was also given to the category of o-substituted fluorotoluenes. After general discussion in plenary session, the group split up into two subgroups. The task of the first subgroup was to tabulate the physiiochemical properties of the selected halogenated aromatic compounds and to collate the data on their analytical detection and occurrence in the environment and in food. The second subgroup was asked to review available toxicological and other data on these substances, relevant to an assessment of human health hazards. consideiation was also given by both subgoups to some of the practi- cal problems associated with pollution of groundwater in terms of recogrition, monitoring, control, and treatment of polluted supplies. A special feature of the meeting was that it was convened at short notice in response to a request for guidance. It was thus accepted at the outset that the scientific data made available to the group in the form of background papers could not be based on exhaustive literature reviews, and might, there- fore, be incomplete in some respects. It was recognized, however-, that the group should make the best use of the information available, where necessary using expert judgement and extrapolation, in order to develop pragmatic guide- lines. A more rigorous, strictly scientific approach was not felt to be particular-ly helpful, since its use would have precluded any conclusions ir instances where desirable information was lacking. 2 II REVIEW OF INFORMATION HALOGENATED TOLU[,NES Major uses and environmental occurrence Halogenated toluenes comprise a range of toluene derivatives substituted in one or more positions of the aromatic ring or in the methyl group. They are used, directly or indirectly, in the manufacture of dyes, explosives, fo9ms, coatings, plasticizers, food preservatives, herbicides, and other products. Major uses of the various halotoluenes are as follows: a,a,a-t ic hloro to lu e ne : pharmaceuticals, dyes, agricultu ral chemicals ; p-chlorotoluene: pharmaceuticals, dyes, solvents, agricultural chemicals; o-chlorotoluene: pharmaceuticals, dyes, solvents, agricultural chemicals; a,a,a-tifluoro4-chlorotoluene: pharmaceuticals, dyes, solvents, disin- fectants; a,a,a-tifluoro4-chloro-3 -nitro toluene : pharmaceuticals, dyes ; a,a,a-trifluoro4<hloro-3,5-dinitrotoluene.' intermediate for the synthesis of herbicides. Information on the environmental occurrence of this class of chemicals is generally either limited or completely lacking, and therefore it was not pos- sible to evaluate wr:h any accuracy the extent to which they are dispersed in the environment (Table l). Since, however, many of the compounds have low boiling points and are moderately soluble in water, they can be trans- ported relatively easily in air and water. In consequence, a wide environmental dispersion can be expected, particularly near manufacturing plants, where toluene is transported or where contaminated end-products are used. Such information as exists on the a-substituted fluorotoluenes relates to investigation of the episode of pollution in Vicenza Province, first recognized n 1976. The main source of the environmental contamination was a chemical plant producing fluorotoluene derivatives, such as dinitrochlorocg,o-tri- fluorotoluene, an intermediate in the synthesis of dinitroaniline herbicides. Analysis of water samples from wells and aqueducts by gas chromatography and mass spectrometry showed the presence of 4-chloroqg,o-trifluorotoluene, J Table 1. Physicochemical and environmental data for Physical properties Odour threshold Chemial Melting Eoiling Vapourprel!ure (mmHg ar 2O"C) Partition cefticisnt {log P octanol/waterl Solubil i ty in water (mg/l at 2O'c) point point('c) ('c) Air Water(ms/l){mg/m! ) Halobnzq6 monochlorobenzened -45 53 - t7.5 17 132 173 r79 213 N 0.6 '| <1 <l 0.@@1 2.8 3.38 5m 90 1m <30 0.5-8 <90 <3m 0.1 0.mo3-0.03 0.0r 0.m5 pdichlorobenzene odichlorobenz€ne 1, 2,4-trichlorobenz€nea 1,2,4,5-tetrachloro- benzene hexachlorob€ozane 4.23 138 228 $.6 70-72 -t4 - 10.4 7r.5 83 246 320 6.0 r.8 1.9 t.9 2.1 2.4 0.007 0.13 3.0 monobromobcnzenei r56 30 pdrloroaniline o-chloroaniline m{hloroaniline 3,4-dichloroaniline 230 m8 230 212 0.0t 5 5300 <0.1 <0.1 0.05 p-chloronitrob€nzene p€ntachloronitro- benzene 242 0.t o.o1 -0.2h Halophenols 2,4dichloroph€nol' 2,4 5'trichlorophenol 2,4,6-rrichlorophenols pentachlorophenol 45 62 68 r90 210 252 244 310 1.0 (53'C) 0.1 3.08 3.75 3 -3.7 3.8 4600 lo 0.m2-0.2 o.2 0.3 t.6 o.g2 -2.5 0.000r Halotoluenes o-chlorotoluene (bonzyl- chloride) o.o,c-trichlorotoluene p-chlorotoluene o-chlorotoluene qA,a-trif luoro4.chloro- toluene c,o,o-trif luoro4-chloro- 3-nitrotoluene c,c,o'trifluoro4-chloro- 3,5'dinitrotoluere - 3!) -21 7 -u 179 221 162 159 1.0 1.5 493 slightly slightly 90 38 26 36 139 222.6 >240 10 (40"c) 5.8 <1 <0.0156 a Can be tound during chlorination of drinking-wata. b With advaned analytical lechnique. c lndoors. d Fish tst in mq/ks. e Fish oit. 4 14 the halogenated aromatic compounds reviewed Analytical sonsitivity Environmenlal conentration me6ured Water (/rgll)Water Air Tissue k4/l) (ms/mr ) (ms/ks) (pslm3 )Air Food(mg/kg) Drinking Surfae 0.3 0. r2 0.06 0.01 0.5 0.04 -0.2 0.02-0. I 0.3 -5 0.2 - 13 <0.1-6 35 't5 30 <0.m5-5b r,,*'-1iLr" <o.oo5-3 2X1o{- O.O5 <0.005-3 < 0.005-0.3 <0.01-0.4 o.1d o.o1 -0.5e 0.0r < 0.006 found < 19 0.1 - 1. t9 0.1 -0.7 o. I - r.1c 0.7 1 <1 <0.1 <10 36 <0.05-0.6 <0.04-0.6 <0.03-0.6 0.1 - r00.265 1.4 < 0.01 -0.015 <0.01-0.020 o.o5€0.oi o.60-450.01 o.7o- 56.0, / HCB residues have been found in f@d groducG, human lat. blood, and milk. 9 p- and a-chloroaniline. h Refen to chloronitrobenzsne (isomer unspecilied). I Analyses of groundwater from the polluted rogion in Vicenza Province. 0. I 0-0.04 0.5 0.5 0.5 0.5 0.5 0.5 0.5 5 I I 3-nitro4-chloroc,o,o-trifluorotoluene and 3,5dinitro4chloroa,a,a-trifluoro- toluene in the ranges of 0.05-90pgll,O.6-45Opg[, and 0.7-56pellof water, respectively (1). Only a low concentration of the mononitro derivative (0.6 pg/l) was detected in drinking-water from the piped system. Regular monitoring of well-water over the past 3 years has shown a steady decline in the concentration of 3-nitro-4<hloroo,o,c-trifluorotoluene to the present maximum level of ap- proximately 2OO pgll, and of 3,S-dinitro4 chloro and 4chloro derivatives to I and 45 pg/I, respectively (Gambaretto, G., personal communication). It has been shown (2) that 4-chloroa,o,o-trifluorotoluene is strongly bound to soil. This behaviour is similar to that of trifluralin (o,o,o-trifluoro- 2,6-dinitroJ/,1/-dipropyl-p-toluidine). One year after the application, 69% of the applied radioactivity was present in the top 15 cm of soil; after 3 years, some 43% remained in this layer. Like that of trifluralin (-7), the breakdown of the 3 pollutants mentioned above probably follows 2 pathways, depending primarily on soil moisture and oxygen availability. Under anaerobic conditions there is rapid progressive reduction of trifluralin followed by dealkylation, whereas aerobic degradation proceeds more slowly, first by dealkylation and then by reduction of the nitro goup. Physicochemical properties The available physical properties of the halotoluenes considered are shown in Table l. These halogenated toluenes are liquids of low vapour pressure and are slightly to readily soluble in water. There are no data available concerning odour thresholds. Toxicological properties The o-halogenated toluenes and their nitro derivates, as well as ring- halogenated toluenes are a class of compounds that, in large doses, may cause damage to the central nervous system (CNS). This effect has been observed in man (4) and in experimental animals (5). The compounds in this class are also irritant to skin and mucous membranes. The presence of one or two nitro groups in the benzene rhg of the o-halogenated toluenes alters both metabolism and toxicity. A plominent specific characteristic of the toxicity of such com- pounds is their methaemoglobin-forming activity (6,7). Such activity is also conrmon to a number of nitrobenzenes, nitrotoluenes, anilines, and amino- phenols (8). The main toxic properties in animals and exposure limit values (where available) are listed in Table 2. oC hloro to lu ene ( b e nzy lch loride ) This material is slightly toxica on acute exposure. c-Chlorotoluene and other reactive members of this class are skin irritants and would also be expected a The classification of acute toxicity throughout this report is based on the 5ystem of Hodge & Sterner (9). 6 'aooo@oIEaoooxoB .ql -9n5;s'oSo.EE . = o o$o69I-go'coEtr9.= o P9 . = o 39ocEao'6!ooo=s<az>oFEEooIoo.9oo.EcEtof9EGE) B EE >!o !2o9-A .:6= cCY :o .= P60 _9Ay? s 8i Bob > x6 .:;a 'Zp.= sr69 cYl 5F3 =68 aQa o i98""9U' .* .u; E.E x'o :orc o o ^ EFLO o o ^ G P EFLA ocBocJtrf o.fo8e>-9 vcOao5B e O Er E<o - -:.o I t,ci oti! oLo e?F=li! 0q-: o c?6 rq^>tr ,o o @ .a5 ryr= 9i i o - - - r: q t.: i d-.E ; iJEE oco O J .E9 .s9 !ohlo?:q. ;dtdrt c;cIcl c!ocx= .iegE9r'; a .: o -t Co 'E8 = e=G ofEco.gc3ocICf,;vcf E.ou')fc, Bocvcf c;Cxa aaah3No a ^at<U' U' 33u?gon c;ovtrl c!ocJcf (nz() cioE!c c3Jc5 ?NC I i3'- (r):itse6Sts ocofo)G oofoooE tr;ovlc;ovcl;ocvclc3oc!c) U)z(J 8aClrFoe- o9J- P-o F 6 , ', = d6-Yo=c(f,oo=It oolol= oe6Eo6J tv?6a,=d_9 d<t ,7 a .e . € Q Ea -a = E I E> E O - <9o:.9cgc'6G(.)a:qcoIf=9AFO>EaJ, 6 5.Ed^ t J-- faSo.9 E ts x- raO ?E _ 3.9 E3 3 sle3:E: " EgI;.9EoEo .!EofIo.xo!tr(E(Eo!:pxo6E'E(o;ocoo'1CO)oo)o)oEIc.iq,-ooF to be sensitizing agents and to induce leucopaenia. The q*hlorotoluene has relatively high reactivity and would be expected to interact with macromole- cules; it is known, for example, to react with proteins (10). After absorption, it is metabolized to benzoic and benzyl mercapturic acids, which may be ex- creted either free or conjugated with glycine. Currently, there are no data avail- able as to its teratogenicity or effects on reproduction. Results of mutagenic tests with strain TAl00 of Salmonelh typhimaium indicate that it is weakly mutagenic (11,12)- Preliminary tests indicate that o+trlorotoluenes may induce local sarcomas in rats following subcutaneous injection (1-7). It is currently being tested by gavage in mice in the US National Cancer Institute bioasay programme. It has also been tested in mice by intraperitoneal injection and no tumours were found (14). Effects on man Atmospheric concentrations of l60mg/m3 caused severe irritation of the eyes and respiratory tract; 50- 100 mg/m3 caused immediate lachrymation and twitching of the eyelids; and 5 minutes'exposure to 6-8mg/m3 caused slight conjunctivitis. Benzyl chloride production workers showed a greater tendency to respiratory illness and dermatitis (15). The odour threshold has been determined to be 0.25 mg/m3 (lO;. Exposure limits for the workroom environment vary from 0.5 mg/m3 (USSR) to 5 mg/m3 (USA) and are based on the irritant effects of the com- pound. a, a, a-T i c hlo ro t o lu e n e This material is moderately toxic in acute exposure. At high doses or vapour concentrations it is irritant to skin and mucous membranes and acts on the CNS as a narcotic. After inhalation of l00mg/m3 for 2 hours daily for I week, rats became aggressive; haematological changes found included a teduced haemoglobin level and leucopaenia (1 7). Metabolism of c,c,c-trichlorotoluene is expected to differ from that of the o-ctrlorotoluene. The ring structure of the former compound is more stable and oxidation of the substituted methyl group is thus less likely. No data are currenfly available concerning either teratogenic or repro- duction effects of c,o,o-trichlorotoluene on animals. Results of tests with Salmonella and E. coli indicate that it is mutagenic (18). Effects on nan An increase in the incidence of lung cancer has been reported in workers exposed to a mixture of toluene, o,a,c-trichlorotoluene and benzylchloride(19). The exposure limit for o,o,a-trichlorotoluene in the working environ- ment has been set in the USSR at 0.2 mg/m3. 8 4 -C h lo ro - a, a,a- t i flu o ro t o lu en e The acute toxicity of this material is low. Preliminary experiments with animals have been reported (see p. I l). Pharmacokinetic data for the com- pound are not available, but would be valuable in assessing the possible effects of the o-halogentated toluenes. No data are currently available on the effects of the compound on re- production and fetal development. The Ames test, with and without in vivo and in vitro activation, indicated no mutagenic effects (20). DNA repair synthesis in human epithelial cells was altered at levels oi I pl/ml (1,21). No data are available on chronic effects or carcinogenicity. Effects on r/an Repeated exposure has been observed to cause dermatitis and extended inhalation may cause irritation to the nose and throat. To date, no exposure limit has been established for the compound. 4 {h lo ro -3 -ni tro r.,a,a- tiJlu oro t o lue ne Acute symptoms observed in experimental animals after exposure to the compound, e.g., the appearance of methaemoglobinaemia, are similar to those expected after exposure to other aromatic nitro derivatives. While adequate data are not available, the relative LD56 values may provide some indication of the likelihood of methaemoglobin formation. Preliminary in vitro experi- ments with isolated rat liver mitochondria indicate a disturbance in mito- chondrial respiratory control (22). lf this effect were to occur rn uiuo, it might contribute to the anoxic symptoms. The presence of the nitro group alters the metabolism of the other ring substituents. Likely metabolites would be nitroso, hydroxylamino, and amino derivatives. The chloro group would be activated and thus more easily sub- stituted. [n addition, it is possible that nitroso derivatives may be formed, and that they be mutagenic and/or carcinogenic (23). Results of the Ames test, both with and without in vivo and in vitro activation, were negative (20). However, results of DNA repair synthesis ex- periments were reported to be positive (21,24). No data are currently avail- able on the carcinogenicity of the compound. Effects on ftwn For information about possible effects on man, see p. I l. Although the relevant data are lacking for 4+hloro-3-nitro<,c,o-trifluorotoluene, animal experiments with the closely related compounds 3-nitro-o,o,o-trifluorotoluene and 3-aminoo,c,o-trifluorotoluene have led to the recommending of limit values for water of 0.01 mg/l and 0.02mgll, respectively. 9 4 -C hlo ro -3, 5 4 initro-a,ot,ot-t iflu o ro t o lu e ne The acute toxicity of this material is low to moderate; acute exposure results in irritation to skin and mucous membranes. Preliminary in vitro experi- ments with isolated rat liver mitochondria indicate that the compound in- hibits mitochondrial respiration and also several mitochondrial enzymes at levels of 0.25 mmolll(22). The behaviour of the compound is expected to be similar to that of the mononitro analogue but it shows greater reactivity. The reaction mechanisms expected are: (a) reduction of the nitro group, (D) nucleophilic substitution of the chloro group, and (c) nitrosation. The results of both the Ames test, with and without in vtvo and in vitro activation (20), and the DNA repair synthesis test were negative (/,2/). No data are currently available concerning the carcinogenicity of the compound. Effects on nun For information about possible effects on man, see p. I l. a,a"a-Tiflu oro -2, 6 4initro-N, Ndipropy l-p+ o luidine ( tri/lumlin ) Acute toxicity of trifluralin in animals is low. Oral LD56 values in rat and mouse range from 0.5 to 5 g/kg body weight (25-28),while the intraperitoneal LD5e has been reported as 4.8 g,/kg body weight (29). No adverse effects were observed in studies in which rats received a diet containing 2 g trifluralin per kg food for 2 years and dogs received doses of l0mg.kg-r'd-r for 3-4 years (25,30). Oral administration of trifluralin (dis- solved in oil) to rats for 6 months induced several adverse effects including decreased haemoglobin levels and erythrocyte counts and distropic changes in liver, kidney, and cardiac tisue (3). From this study exposure limits of 0.55mg.kg-r.d-r were determined. In the US National Cancer Institute bio- assay programme, trifluralin increased the incidence of liver carcinoma in hybrid female mice (32). However, the possibility that the trifluralin used in the test was contaminated with iy'-nitroso compounds prevents definitive in- terpretation of the data. The results of numerous mutagenicity tests, as well as the DNA repair synthesis test, were negative for trifluralin (33). Effects on ilwn In general, adverse effects of dinitroaniline herbicides in humans have been few and minor (34). Workers with extensive exposure to trifluralin, how- ever, have developed dermatitis and hypersensitivity to light (35). Recommended levels for trifluralin in food are currently l50pg/kg in carrots and oleaginous seeds, 50pg/kg in vegetables and l0pg/kg in cereals(Italian) and an acceptable daily intake (ADI) of 0.1 mg-kg-r.d-1 has been recommended by the US National Academy of Sciences. In the USSR, the ex- posure limit for the occupational environment has been set at 3 mg/m3;a level of 0.3 pg/l is permitted in nonpotable surface water suitable for fish farming. l0 Exposure to contaminated water or air Water samples both from wells and from industrialwastes were tested. After 2 weeks' ul libirum administration to rats of contaminated well-water containing 45O 1tgl| of 4<hloro-3-nitroc,o,c-trifluorotoluene, 56 pgll of 4chloro-3,5- dinitroa,e,o-trifluorotoluene and 56pgll of 4clrloro+,o,o-trichlorotoluene, none of the original conrpounds were recovered in the urine (level of detection 0.5 pg/l). The administration of single doses of concentrated contaminated well' water to rnice (equivalent to aOOpglkg of the 3 contaminants, i.p.), rats (equivalent to 20 pglkg of the 3 contaminants, i.p.), and rabbits (equivalent to 20 pglkg of the 3 contaminants, i.v.) did not cause any deaths or macroscopic, clinical, or pathological symptoms during the following l0 days (see Silano, V. et al., Annex 3). Subacute oral toxicity studies (21 days) were carried out on 3 water samples using 90-day-old rats (24).Two samples were of washing water frorn the chemical plant producing 3,5dinitro4chloro-a,o,o-trifluorotoluene and the third was from local wells. Effects were seen with only one of the two samples from the chemical plant. The effects were lowered body weight and food intake, decreased serum lactate dehydrogenase activity and p-globulin levels, and decreased haematocrit, haemoglobin and red blood cell counts. The sample contained 10.4g of ether-extractable organic material and was of a heavy red colour; 3,5-dinitro4-chloro+,o,c-trifluorotoluene was present but was not quantified. Under the experimental conditions used, the rats received organic material at the rate of 776 mg per kg body weight per day. Effects on ftutn Local factory workers have been exposed to trace amounts of a mixture of halotoluenes in the atmosphere in typical concentrations of, for example, 0.05 - 0.7 mg/m3 of 4chloro-3, 5 dinitro-o,a,o-trifl uorotoluene, 0 - I mg/mr of 4-chloro-o,c,e-trifluorotoluene, and 0-l.4mg/m3 of 2-fluorotoluene. They have been checked routinely for haematological parameters and clinical symptoms at 6-monthly intervals in the last 2years, but no major pathological changes, such as blood chemistry changes, clinical signs, or dermatitis, have been observed dur:ng this period. Epidemiological data (see Annex l) on the general population exposed to the same materials in contaminated water have proved difficult to evaluate be' cause of frequent changes in water sources and the use of mineral water. TIALOGENATED BENZENES AND ANILINES Major uses Halobenzenes are widely used in the chemical industry. Estimated worldwide production is of the order of 900 000 t/year, including 600 000 t of monochloro- benzene. Major uses of the various representative compounds are as follows: ll monochbrobenzene: solvent, flotation medium, important intermediate fo r dyest uffs, pes ticides, pharmaceuticals, perfumes ; p4ichlorubenzene: moth repellant, deodorant, important intermediate for dyestuffs: o4ichloru benzene : solyent, important intermediate for dyestuffs, pesti- cides; 1,2,4-trichlorobenzene: solvent, dielectric fluid, heat-transfer medium, intermediate, insecticide ; 1,2,4,5+etrachlorobenzene.' intermediate, e.g. for 2,4,5-trichlorophenol production; hexachlorobenzene: wood preservative, fungicide, intermediate, e.g. for pentactrlorophenol production ; mo no b romo b enzene : solvent, petrol additive, intermediate ; 4 - c h lo ro aniline.' inte rmediate fo r d yestu ffs and pharma ce u tic als ; 2 - c hlo roaniline.' intermediate fo r dye stu ffs and pesti cides ; 3-chbroaniline.' intermediate for dyestuffs and pharmaceuticals, insecti- cide; 3, 44 ic h lo ro anililw : tnte r me diate for he rbicides and dyestu ffs ; 4 -chloro ni tro b enzene : intermediate for pharmaceuticals and dyestu ffs ; pe ntac h b ro niffob enz ene : fungicide, intermediate. Physicochemical properties The available data on the halobenzenes selected for the present review are summarized in Table l. The compounds range in appearance from mobile liquids to crystalline solids; water solubility ranges from high to very low. With increasing halogen substitution in the aromatic ring, the melting and boiling points increase, while the vapour pressures decrease correspondingly. Water solubility is reduced and solubility in fats is augmented with increasing halogen content. The chlorobenzenes are the best known members of this class of com- pounds; they represent a complete series - from monochloro to hexachloro -in which chlorine can replace hydrogen in each position in the benzene ring. They are normally produced through direct chlorination of benzene; by extending the reaction time, the proportion of more highly ctrlorinated molecules is increased. Each of the three theoretically possible isomers of di-, tri-, and tetrachlorobenzene is produced by this means, although in vary- ing proportions. In normal production practice, the different compounds are separated by distillation. As a result the degree of purity varies, especially in the separation of isomers. Differences between reported results on what are apparently the same compounds may well be due to such variation in composition. t2 The chlorobenzenes show a clear gadation of physicochemical prop- erties, related to the degree of chlorination. Within this general gradation, there are small differences between isomers that do not show any consist- ent pattern. The ring-substituted chlorobenzenes are quite different in structure and properties from benzene hexachloride, which is an addition product more cor- rectly described as hexachlorocyclohexane, and also from side+hain substi- tuted derivatives such as chlorinated toluenes. Fluoro-, bromo- and iodobenzenes are also known, but have much less economic importance. fu might be expected, chloro compounds are inter- mediate in physical-chemical properties between their fluoro and bromo analogues. Chlorobenzenes range in appearance from mobile liquids to crystalline solids; all are denser than water. They are lipophilic, with no tendency to ionization; solubility in water is significant in the case of monochlorobenzene, but decreases rapidly with increasing ctrlorination. The octanol-water par- tition coefficient increases sharply up the series in parallel with decreased water solubility. In spite of their comparatively high boiling points, the mono and the di isomers are very volatile, even from dilute solutions in water; volatility de- creases with increasing chlorination. The chloroanilines are normally produced from the corresponding chloro- benzenes via the nitro compound, which is then reduced to the amine. They are similar to aniline in many of their properties, being freely soluble in water, basic in nature, and oflow but significant vapour pressure. Environmental occurrence Although most of the compounds are employed as intermediates in further synthesis, large proportions of some of them are used for purposes tlat assure their rapid dispersal in the environment. In spite of their high boiling point and appreciable water solubility, mono- and dichlorobenzenes are very volatile and it is estimated that perhaps 300 000 t of monochlorobenzene, 40 000 t of odichlorobenzene and 80 000 t of p-dichlorobenzene are released and distributed in surface water and the atmosphere each year. Most of the tri- and tetractrlorobenzenes are used for further synthesis, but unknown quantities are present as impurity in dichlorobenzenes and more are lost as a by-product or unconverted reactant in effluents. Pentachloronitrobenzene (PCNB) is used almost exclusively as a fungicide, as is some hexachlorobenzene (HCB);they are thus widely distributed in the environment. Most of the HCB "produced", however, originates as a by- product in a wide range of chlorination processes and is lost as a waste. PCNB and HCB both have low but finite solubilities in water and low vapour pres- sures; they adsorb strongly to particles, but there are no data available on their partition between air, water, sediments, and soil. The chloroanilines are polar, of appreciable water solubility, and of low volatility;they therefore tend to stay in surface or soil water. l3 A final source of halogenated compounds in surface and drinking-water is chlorination. The quantity of chlorine used for disinfection of potable water and sewage, and in bleaching paper and textiles, is probably about 5 00 000 t/year. As the chemistry of the reactions of chlorine or hypoctrlorite in dilute aqueous solu- tions is very poorly understood, however, it is difficult to make any estimate of the quantity ofchlorinated by-products resulting from these applications. Toxicological properties The main toxic effects of chlorobenzenes in animals are listed in Table 3. Acute toxicity is generally low; it increases from monochlorobenzene to the tri isomers, then falls steadily to hexachlorobenzene. All members of this class affect the CNS and also cause irritation of mucous membranes. Monochlorobenzene Chlorobenzene exhibits only low acute toxicity in animals, whether administered orally or by inhalation. Chronic effects noted include increased liver and kidney weight, with some histological changes, but only at doses approaching lethal levels. There are insuffient data to define any dose-related response (36-42). The compound is readily metabolized to chlorophenol, which is then excreted as a conjugate (28,43). There has been a report that it is not muta- genic to Aspergillus (44), but other data on mutagenicity, carcinogenicity, and teratogenicity are inadequate. Effects on man Chlorobenzene shows some depresant and narcotic effects when inhaled. Because of the high volatility of the compound, this is the only significant route ofexposure. Occupational exposure limits vary from 50 to 350 mg/m3. It has been suggested (40) that the 350-mg/m3 level is too high and that 50 mg/m3 would be more appropriate. The criterion for the standard is qystemic effects. Oral ingest;<-rn via food and water is unlikely, owing to the strong deter- rent taste. The USSR standard for water of 0.02 mg/l is based on organo- leptic properties. Dichlorobenzenes Although three isomers are known, only the ortho and, parc isomers are commonly used. The proportion of the meu isomer is always low. The compounds are of low to moderate acute toxicity, whether by in- halation or oral administration; sublethal levels cause irritation of skin and mucosa. Subacute and chronic effects reported include damage to liver and kidney, CNS depression, and haematological abnormalities at dose levels close to lethal. There are insufficient data to establish dose-response rela- tionstrips (3 6 - 3 9,45 4n. t4 IgEo.FJI !:3PEEi6l5 alooEi2o - .PEB E:.=! o? S I i,9 E P 3oI a N l o -3 a N !0 o -; ii_zzoeSEoo ;to.6 a -a 6<666 ll3oo o FCccc ;!;oo o trli.i8P3 c lEe ^?SEg9 cc c Qee o o o -9-9! 'i -i 'a o n6 N N N = - a *< r92 R88Ii alo]i.d! 2EeJE i ;^^ sEs 2gr R38 !gE'gu?tsnoo3_9,99 gioPzto . q'! 9P8JEI 9EE g.ig '4qqE!9 c-t-9.9: . . .3 i;:-.id2.E H tE a N l o -3 a .a a @ EA 353 838i? .!!e8!,:EB.3-9 8E- UOEEE <i,E&'6o,q=E .:Eq)=oo.xo)!GG(o!.l.9xoG.Ec(!;q,coNq)!oo()aig-o(Ut- :!'Eie-85< 3!a 1,9i9Eo l Dichlorobenzenes are fairly readily metabolized to the corresponding di- chlorophenols and are then excreted as conjugates. The more pronounced liver damage caused by the o-dictrloro isomer has been associated with a greater tendency for it, or its metabolites, to bind to liver proteins. The compounds were apparently negative in bacterial mutagenicity tests (Ames). US National Cancer Institute assays for carcinogenicity are in prog- ress on both o and p isomers Q6,a$. Effects on man Sublethal effects on man exposed to dichlorobenzene vapour include CNS depression, some lung and liver damage, and blood disorders. One case study strowed the occurrence of leukaemia (48), but the evidence is incon- clusive. The major route of exposure for man is probably inhalation. There are insufficient data on skin absorption to decide whether this is also significant. Occupational exposure limits vary from 20 to 450mg/m3. The lower standard (USSR) is based on skin irritation. Sigtificant absorption from food or water is unlikely, owing to the strong taste and odour imparted by these compounds. The USSR standard of 0.002 mg/l for drinking-water is based on organoleptic properties. Data are inadequate to determine which route of exposure accounts for the high levels of p-dictrlorobenzene found in human tissue in Japan or to make any further comments on'the existing air and water standards. Tlichbroberuene Of the three isomers known, 1,2,4-trichlorobenzene is the one commonly used, but many of the available data refer to tests on mixtures. Acute toxicity is low, both by oral administration and inhalation. Sub- acute effects have been reported in mammals exposed to atmospheric con- centrations of 150-220m9/m'. These consisted of liver damage and, in par- ticular, porphyria (49,5 0). Similar liver damage has been reported following dietary administration at sublethd levels, but no porphyria orjaundice was observed (5/-53). No information on mutagenicity, teratogenicity, or carcinogenicity has been found. Metabolism to trichlorophenols occurs, but slowly. Effects on nwn Trichlorobenzenes caused marked irritation of mucous membranes over short periods of exposure, in atmospheric concentrations as low as 25 mglmt. The ambient air standards are set on this basis. The odour threshold is about 22mglm3. No studies have been made to determine the exact levels at which tri- chlorobenzene vapours cause membrane irritation when inhaled over long periods, nor are any data available on whether porphyria occurs in man. l6 The level of 0.02mg/l acceptable in water in the USSR issetonthe basis of organoleptic properties. Atmospheric exposure limits for the occupational environment are 36 and l0mg/rn3 in the USA and the USSR, respectively. There are insufficient data to decide whether oral intake of trichloro- benzenes could constitute a hazard. Te trachlorobenzenes The three isomers are all known, but only 1,2,4,5-tetrachlorobenzene is used to any sigrificant extent (as an intermediate in the production of 2,4,5- trichlorophenol). Acute toxicity by oral administration is low (37). Low vapour pressure precludes signifi cant inhalation. Continuous administration in the diet at levels as low as 0.005 mg.kg-t .d{ produces CNS effects, liver damage, and haematological abnormalities (54). Effects on nan No case histories are recorded, but oral ingestion could be hazardous. Hexachktrobenzene Acute toxicity by oral administration is low, but chronic dietary exposure leads to CNS effects, liver damage, and severe porphyria (5556) at levels of approximately 5 mg.kg-t .d-t. Hexachlorobenzene (HCB) is metabolized only slowly and accumulates in fatty tissue. lrvels of up to l0mg/kg have been recorded in the fat of farm animals fed on diets containing HCB, and up to l00mg/kg in wild birds and their eggs. A halflife in tissue of 60 days has been quoted (38). Metabolites include tetra- and pentachlorobenzenes and penta- chlorophenol. Effects on rton A major episode of poisoning occurred in 1955-59 following the con- sumption of HCB-treated wheat. Some deaths resulted, but the major syn- drome was porphyria. The estimated intake of HCB was 0.7 -3.0mg.kg-t .d-r. Accumulation in the fat and milk of humans is now frequently reported at levels of up to lOmg/kg dry weight. The only possible route of intake is through food and water, as vapour pressure is extremely low. A provisional ADI of 0.001 mg.kg-r.d-1 has been set, based on a safety factor of 1000 (-?4. No recommendation for drinking-water levels has been made; HCB could, however, logically come under the chlorinated pesticide standard of l0pg/I. Bromobenzene This material has some uses as a chemical intermediate. The very few data available suggest similarity in toxicity to that of chlorobenzene. l7 Oral LD56 values are low (3.2 g/kg in the rat; 2.7 glkgin the mouse) (39). Sublethal effects include irritation of lung and mucous membranes, dam- age to liver, and CNS depression. Bromobenzene is absorbed through the skin, is negative in mutagenicity screens, and is not carcinogenic in animals. Effects on rwn The atmospheric exposure limit in the USSR for the working environment is 3 mgim3. This is based on the irritant properties of the material. Pe n ta chlo ro nit rob enz ene ( PCN B ) PCNB is a fungicide similar in molecular structure to HCB and penta' chlorobenzene; it is always contaminated by both of these substances, at the percentage level. The acute oral LD5s in rats is low (1.2-1.6g/kg).As the vapourprcssure of PCNB is very low, inhalation toxicity does not occur (38). Subacute and chronic toxic effects have not been observed, even at high doses. The compound is metabolized to a sulfur conjugate and pentachloro- aniline, but most is excreted unchanged in the faeces. While there is no build' up of PCNB in tissues or milk, accumulation of the HCB and pentachloroben- zene contaminants does occur. PCNB gives negative results in bacterial mutagenicity screens' and does not affect reproduction. It is, however, a suspected carcinogen and is tera- togenic in mice when administered at a dose level of 0.5 g/kg during gestation. Effects on run No adverse effects have been reported. The maximum residue level in the USA is set at 0.1 mg/kg, except in peanuts for which the limit is I .0 mg/kg. No ADI has been calculated, but any such standard, or water quality criterion, will be based on the risk of carcinogenicity. The atmospheric exposure limit in the USSR is 0.5 mg/m3 for the working environment; for ambient air, a concentration of 0.006mg/m3 has been set as a 24-htime-weighted average, with a cqiling of 0.01 mg/m3. Chloroanilines The most characteristic biological effect of this group of chemicals is the formation of methaemoglobin. This property is strared by arylnitro compounds such as chloronitrobenzenes, and may be due to the action of a common meta' bolite (posibly a nitroso compound). pChbroaniline Oral LD56 values (100-400mg/kg depending on species) indicate moder- ate acute toxicity in experimental animals. In vapour or aerosol form, p*hloroaniline is absorbed both by inhalation and through skin. lt is impossible to separate the effects following absorption l8 by the two routes. The principal acute effects are methaemoglobinaemia, followed by cyanosis and CNS paralysis. The level of methaemoglobin formed in blood is dose-dependent. Thus, methaemoglobin levels of 3% and 6Wohave been found in the rat after oral administration of, respectively,4 mg/kg and 136 mg/kg (58). Chronic toxicity is also manifested primarily by methaemoglobinaemia, but some damage to liver, spleen, kidney, and bone marrow has been found, probably as a consequence of methaemoglobinaemia. Like other aromatic amines, p-chloroaniline is metabolized to the corres- ponding phenylhydroxylamine which is then oxidized to nitrosobenzene (59). No data are available to indicate that p-chloroaniline has carcinogenic activity. Effects on mon Dermal and inhalation effects cannot easily be separated owing to rapid skin absorption of the vapour or liquid. As in animals, exposure to p-chloroaniline produces methaemoglobinaemia, cyanosis, dizziness, respiratory paralysis, and coma (60-62). Human subjects deficient in glucose 6-phosphate dehydrogenase are more susceptible. Cyanosis has been found in workers exposed to atmospheric concentrations of 58- 63 mg/m3 of p-chloroaniline (63). Exposure standards for the working environment vary from 0.05 mg/m3 (Yugoslavia) to 5 mg/m3 (Romania) and are based on skin irritation. The limits for ambient air in the USSR are 0.01mg/m3 (24-hour mean) and 0.04mg/m3 (ceiling value). The maximum concentration permitted in drinking-water in the USSR is 0.2 mg/I. These standards are based on the toxic properties of p- chloroaniline. 3,4-Dichloroaniline Oral LD5s values (650 and 750mg/kg in rats and mice, respectively) indicate that this material is of moderate acute toxicity in animals. A dermal LD5s value of 700mg/kg in the cat indicates ready skin absorption. Toxic signs seen after intraperitoneal injection of 3,4dichloroaniline ( 150-600 mg/kg) included CNS depression, a loss ol righting reflexes, and cyanosis (unpublished data). ln chronic inhalation experiments in rats, the threshold concentration for the effect on the CNS was 0.03 mg/m3. No data are available on mutagenic and carcinogenic activity. Effects on man 3,4-Dichloroaniline is absorbed by inhalation and skin contact, producing methaemoglobinaemia, cyanosis, and CNS paralysis. The exposure limits for the USSR are 0.5 mg/m3 for the working environ- ment, 0.0 l mg/m3 for ambient air, and 0.05mg/l for drinking-water (the last based on organoleptic properties). t9 CHLOROPHENOLS Major uses The chlorophenols selected for review are used either as pesticides or as intermediates in their manufacture. The specific uses of chlorophenols are as follows: 2, 44ic h lo ro p he no I : intermedia te in pes ticide syn the sis ; 2,4,5-tichbrophenol: fungicide, intermediate for 2,4,5'T and its deriva' tives; 2,4,6-trichlorophenol: fungicide, general antiseptic in wood and textile industry; pentachbrophenol : fiin$cide and insecticide. Physicochemical properties Chlorophenols are, in general, solid compounds that are readily soluble in water. They are characterized by an unpleasant smell and the odour threshold is low (see Table l). Being polar and of appreciable water solubility and low volatility, they will tend to stay in solution in surface or soil water' Environmental occurrence The worldwide production of halophenols is of the order of 100 000 tiyear; the major ones produced are 2,4-dictrlorophenol (approximately 50 000 t/year) and pentachlorophenol (approximately l4 000 t/year). Chlorophenols are found in surface water in relatively small amounts, owing mainly to the release of chemical plant effluents. The Presence of penta- chlorophenol in drinking-water results largely from chlorination for the pur- poses of disinfection. Toxicological properties The main toxic characteristics known from animal experiments are listed in Table 4. Inhalation and skin absorption represent the principal routes of absorption. 2,4-Dichlorophenol This compound is moderately toxic after oral administration; acutely toxic doses affect mainly the CNS and liver. It is believed that the compound is readily metabolized to hydroxyphenols and conjugated with glucuronic acid and monchloromercapturic acid, prior to excretion. In bacteria, however, the metabolic pathway could involve opening of the ring structure. 20 tcEco'tc a "'o9 .jbCE;q9dEO<o AQ 2t iE^ - ' _ a * O bQ =U' + E) Z') s:ois ! o5'E _ a > o ogcii E36.a;ts6o3 aov)l E.i a5o oE .9!Es aaJ- a < aAa r3-u?oo G(no 6cot .9E , .2 _ 3! EE r E5E.E Poc, '-ootr EEocd oc'6Ec Eag:!= '=bi-dc ,iae=88 p:tsE.ii , EE AE - o oJE.Ex EfuiPzxo 5cEoooEc u?NooEcaooEoN oc!oc ocEoc !ocEocIfEc.Ec !oc ^?EEoooooo @o6coGaoIEo'=@('N 3 a3SE;-Yco6cEoooE.9!ci 8.9 -E=oH€x: U.: o .! E E;- Ee€ 9;P EO E {9-oJ:aoG _ 3.9 E3 e e ai a :s8 " EgI .EIc'6I:ecE=tooEan cot.sf6.9Eto Eo , fooxo)!c(!(E(gT'2.9xoGE.E(,ocoo.!d)(ECoErooIsq,_o(EF I Dichlorophenol has been reported to cause a significant increase in fetal abnormalities (limb aberration) in animals given 75 mg/kg subcutaneously. The compound appears to be negative in mutagenicity studies, but its carcinogenic potential is currently being tested in the US National Cancer Institute bioassay prograilrme. A study of chronic effects in mice showed no adverse effects at a dose level of l00mg'kg-r'd-r over a 6-month period (6r'). This has led to the determination of a SNARLa of 0.7 mg/kg for lifetime exposure. Effects on nan No data were available to the working group. A maximum allowable concentration of 0.5 gg/l for drinking-water has been recommended by the US Environmental Protection Agency on the basis of taste. 2, 4, 5 -Tr ic h lo ro p h eno I This compound is of moderate acute toxicity and affects similar systems and organs as dichlorophenol. Dermal exposure,however, could produce more severe skin burns than the dictrloro derivative. The compound is believed to be dechlorinated and conjugated in the form of glucuronates and/or sulfates, which are excreted. Alternatively the compound may be conjugated as glutathione after nucleophylic attack. While no information is available on teratogenicity, mutagenicity tests on trictrlorophenol give negative results. There are no data on carcinogenicity. No adverse effects were seen in a subacute toxicity study in rats at a dietary concentration corresponding to 0.1 g.kg-t.6-t (60. These data were utilized by the US Environmental Protection Agency in establishing an ADI of 0.1mg.kg-r.d-r. Effects on nwn 2,4,5-Trichlorophenol has been reported to cause irritation of mucosa and skin; chlorurce may also occur. These effects may be due in part to im- purities in the trichlorophenol. The US Environmental Protection Agency has recommended a limit for drinking-water of 0.01 mg/I, based on taste. 2, 4, 6 -Tric hloro p heno I This compound showed carcinogenic effects in rats and mice in the US National Cancer Institute bioassay programme (66). Its presence in the environ- ment and in human tissues may arise, in part, from the degradation of lindane (hexachlo rocyclohexane). a S uggested no-adverse-response level. 22 Pentachlorophenol Pentachlorophenol is the most toxic member of this group of compounds. In addition to other toxic effects, it uncouples oxidative phosphorylation. Acute toxic effects in rats following intraperitoneal administration include disturbance of CNS and cardiovascular functions, and of temperature regula- tion. At necropsy, extensive vascular damage was observed (67,68). Penta- chlorophenol is partly excreted unchanged and partly hydroxylated in the para position, yielding pctrlorohydroquinone which can be conjugated, like pentachlorophenol, with glucuronic and mercapturic acids. Doses higher than 5 mg'kg-r'd-r showed teratogenic effects in rats (69). The compound showed negative results in the sex-linked recessive lethal test in Drosophilo (70). A carcinogenicity study, however, gave inconclusive results, possibly owing to the presence of impurities in the sample tested. This com- ment applies to many other experiments on pentachlorophenol. Impurities differ both qualitatively and quantitatively in different samples of the tech- nical material, but include tri- and tetrachlorophenols and dioxins. Effects on mon There is evidence that factory workers have developed skin irritation following exposure to pentactrlorophenol. Several fatal accidents have occurred in man following percutaneous absorption. Clinical signs of intoxication include skin irritation, extreme temperature elevation, increased respiration rate, loss of fluid, and cardiac arrest; damage to kidney and liver may also occur (71- 73). Severe illness has been observed in infants with se rum pentachlorophenol levels of up to I I 8 mg/l ( 7J). 23 III HEALTH HAZARD: DATA ASSESSMENT HALOCI,NATED TOLUENES The halogenated derivatives of toluene selected for review represent part of a large group of intermediates and end-products of toluene-utilizing pro- cesses. Their main use is in the production of agrochemicals, pharmaceuticals, and dyestuffs. In general, they are slightly soluble in water and are not highly volatile. When the compounds are discharged to surface water atmospheric disper- sion is likely to play a significant role in their environmental distribution but, in view of their volatility, very low concentrations in the ambient air would be expected. Information on their environmental distribution, however, is either limited or lacking. The available information on a-substituted fluoro- toluenes derives from investigation of the episode of pollution in Vicenza Province; otherwise, no data are available on concentrations in air, soil, food, or in animal or human tissues. In terms of LDr6 measurements in animals, the acute toxicity of hal- ogenated toluenes is low to moderate. The risk of acute intoxication in man is thus low. None of the compounds discussed has been shown to be carcinogenic except for trifluralin, for which a positive association between oral administra- tion and increased incidence of liver carcinoma in female mice has been strown. Relatively more is known about the toxicity of octrlorotoluene for which the US National Institute of Occupational Safety and Health has recommended an exposure limit of 5 mg/m3 for the working environment, based on irritation of skin and mucous membranes; the corresponding exposure limit in the USSR is 0.5 mgim3. Workers were exposed for two years to "trace" atmospheric concentra- tions ((l mgim3) of a mixture of a-substituted fluorotoluenes without ap- parent adverse effect. This mixture apparently also contained other chemicals associated with the production process, but its detailed composition is not known. Preliminary negative epidemiological data on a section of the general population exposed to halotoluenes in drinking-water are difficult to interpret in view of the lack of accurate information on exposure concentrations and duration. While no acute toxic effects would be expected as a result of consumption of water containing a-substituted fluorotoluenes, the paucity of toxicological data precluded an assessment of the possible long-term consequence of such 24 consumption, as well as calculation of an acceptable level of the compounds in drinking-water. Nevertheless, the group recognized that rnany drinking-water supplies contain tens or hundreds of organic compounds at the pg/l level, rising to as much as l0pg/1. As far as is known at present, these micropol- lutants in drinking-water do not produce adverse health effects. Therefore, in spite of being unable to recommend a scientifically defensible "safe" level of fluorotoluenes in drinking-water, the group made the practical judgement that if the level of o-substituted fluorotoluenes was of the same order of concen- tration as the other micropollutants (i.e., up to l0gg/l), it would be illogical to reject a water supply on this basis alone if all other supplies were judged "acceptable". If concentrations significantly exceeded the 10pgfl level, how- ever, there would be grounds for rejecting the water supply until further toxi- cological data were available. The above rationale should be applied only in those circumstances in which alternative drinking-water supplies are not readily available and which therefore do not allow time for the acquisition of an adequate body of toxi- cological data. The very limited information available on most of these fluorotoluenes should be expanded appreciably. The group recognized that there is a need for more toxicological research on the elfects of long-term exposure, including studies on carcinogenicity, mutagenicity, and teratogenicity. Emphasis should be given to determining "threshold" or "no apparent adverse effect" levels to provide the basic data necessary for setting environmental standards. Specific recommendations relating to the episode of groundwater pollu- tion in Vicenza Province are presented in chapter V ofthis report. HALOGIINATED BENZI]NES While most of the compounds are used as intermediates in further syn- thesis, large proportions of some of them are used for purposes that result in their rapid dispersal in the environment. Of the chlorobenzenes, the monochloro and o-dichloro derivatives have significant use, perhaps 50% as solvents, while p-dichlorobenzene is used almost exclusively as an odorant and insect repellent. Most of the tri- and tetrachloro compounds are used for further synthesis but they occur in unknown quantities as impurities in dich-lorobenzenes. The whole of the PCNB produced is used as a fungicide, as is some HCB. Mono- and dichlorobenzenes are distributed both in the air and in surface water. Surprisingly high levels of p-dichlorobenzene have been reported in am- bient air (l5pg/m3 outdoors, l00pg/m3 indoors). Tri- and tetrachlorobenzene have not been reported to occur in ambient air. Trichlorobenzene, however,has been lound in surface water and drinking-water as a product of chlorination. Practically no HCB has been found in air and only traces in water. Exposure to vapour by inhalation could be potentially hazardous only in the case of the mono and dichloro derivatives, then only with prolonged 25 exposure at a comparatively high level. The possibility of sigrificant inhala- tion is much reduced in the case of the more chlorinated compounds. Skin absorption is unlikely to be a sigrrificant hazard with any of the com- pounds, but intermediate chlorinates could cause dermal irritation. While oral ingestion is a significant route of entry for the more chlorin- ated compounds, particularly HCB and quintozene, the less chlorinated deriva- tives are too volatile to be present in either food or water. Acute oral toxicity is low to moderate for all members of the group; it rises from the mono to the di isomers, then falls steadily to the hexa. Acute effects following inhalation are more evident for the volatile mono- and di- chlorophenols and a depressant or narcotic effect may be observed. The com- pounds also cause irritation of mucous membranes and exhibit a low odour threshold (as does bromobenzene). Dermal toxicity is very low, although minor local irritation has been reported. Subacute and chronic effects, however, are observed, particularly with the more chlorinated compounds. These may be associated with their tendency to accumulate in fatty tissues. Reported effects include increased liver weight, increased enzyme induction, damage to liver, kidney and the CNS, porphyria, and chloracne. Mono, di, and tri derivatives are all metabolized in mammals to mono- and dihydroxy phenols, probably via epoxide formation. These phenols are then excreted as conjugates. Ease of metabolism decreases with increasing chlorination. In the case of HCB, a dechlorination step is necessary before hydroxylation can occur. The combination of high lipophilicity and a low rate of metabolic con- version would account for the observation of high concentrations of HCB (and also pentachlorobetzene, where it has been measured) in human fat and milk, and in some wild bird and mammalian species. PCNB is structurally similar to, and shares some of the properties of, HCB but is much more readily metabolized, and has not been found to accumulate in tissues. It is contaminated, however, with significant amounts of penta- and hexachlorobenzene, which are formed during manufacture. Monochlorobenzene There are no reports of detection of the compound in ambient air. It can be implied that its concentration in samples analysed for substances such as the dichlorobenzenes would, therefore, not exceed l0pg/m3. The lowest occupational exposure limit is 50mg/m3 (USSR); this is 5000 times higher than the presumed maximum probable concentration in ambient air. The group thus considered that this latter concentration would not present any significant risk, but felt that the highest current occupational exposure limit of 350mg/m3 1US,t; was rather high when compared with minimum effect doses in animal studies. Levels of chlorobenzene of 0.005 -5.0pg/l have been reported in drinking- water in both chlorinated and unchlorinated samples;it is known as a product of chlorination. There are no reports of its detection in wildlife, food, or human tisue. 26 The ADI from water, assuming consumption of 2 litres per person per day, would be 0.01 mg/d or approximately 0.15 pg'kg-t 'd-r. When compared with the order of dietary intake that appears to cause minimal toxic effects in ani- mals, this poses no sigrrificant risk. Chlorobenezene exhibits no carcinogenic, ntutagenic or teratogenic activ- ity. There is thus no reason to suggest that a water quality standard should be based on criteria other than organoleptic properties. The USSR standard based on these criteria is 0.02 mg/I. a-Dichlorobenzene The only reported occurrence of this substance in air is so low as to be only of analytical curiosity. It is frequently found in surface and potable waters, in the latter at concentrations of up to 3 pg/I, where it is not always distinguished from the paro isomer. It has been reported in a sample of fish oil at 0.1 mC/kg. On the basis of an intake of 2 litres of water and l00g fish per day, the calculated daily intakes amount to 0.10 and 0.l0Ug/kg, respectively. In the light of data available from subacute observations on aninrals, this poses no significant risk. The maximunr reported levels in water are of the same order as the USSR standard of 0.002 mg/l, based on organoleptic criteria. As there is no informa- tion on carcinogenic, mutagenic, or teratogenic activity, there is no reason to use any other criteria for residues in flood or water. l{owever, relevant studies are recorrrmended in order to provide adequate data lor definitive safety evaluation. p-Dichlorobenzene This substance is reported at surprisingly high levels in ambient air in Japan (15 pg/m' outdoors, l00pg/m3 indoors), but not elsewhere. It is found in sewage and in surface water and drinking-water, in the latter at concentra- tions of up to 3 pg,'I. p-Dichlorobenzene has also been found in blood and fat of human subjects in Japan, at concentrations of up to l0mg/kg. In the absence ofdata on con- centrations in food, it is difficult to decide whether this residue originates from food or inhaled air. Occupational exposure limits vary from 20 to 250mg/m3, as 8-h time- weighted averages. The lower of these is 200 times higher than the maximum reported indoor air concentration. Daily intake in drinking-water, assuming a consumption of 2 litres per day, is equivalent to 0.l0pg'kg-r'd-r. This is so much lower than thedailyintake associated with biological effects in animals that no risk is apparent. However, in view of the high tissue concentrations found in human subjects for a chemi- cal that would not be expected to bio-accumulate to any sigrificant extent, continued monitoring is recommended. 27 l, 2, 4-Trichloro benzene Trichlorobenzene has not been reported in ambient air. Owing to its irritant action, workplace concentrations are kept low, so that extrapolation of experience from this area is not possible. The substance is frequently reported in surface water and drinking-water, where it is a known product of chlorination. The concentrations found, how- ever, would produce daily intakes well below those leading to biological effects. As there is no evidence of mutagenicity, carcinogenicity, or terato- genicity, there is no reason for adopting criteria other than organoleptic properties for water quality standards. Observed levels are well below the 0.02 mgil recommended in the USSR on the basis of such criteria. The only report of a residue in the fat of fish is at a level unlikely to lead to any risk. Tetrachlorobenzene There are no data on the environmental occurrence of tetrachlorobenzene. Owing to its restricted and localized production, and its us€ in closed systems, the absence of data may be assumed to be due to the fact that it is not present; its high sensitivity to analytical detection would otherwise ensure its identi- fication. Hexachlorobenzene (HCB) HCB is now widely distributed in human fat and milk, especially in parts of western Europe, and in wild species such as birds of prey and marine mam- mals. Since it is not found in air, and in only very small traces in water, the presumed route of intake must be via food. This could well be associated with its use as a fungicide in agriculture. As extensive evaluations of HCB use and recommendations for ADI and tolerance levels are already in progress, the group considered that further recommendations were unnecessary. CHLORINATED ANILINES The main use of these materials is in the production of pharmaceuticals and dyes (p-chloroaniline) and of herbicides (3,4-dichloroaniline). Their occurrence in water is most probably due to the degradation of pesticides used in agriculture. fu they are not particularly volatile, the inhalation hazard at ambient temperatures is low. Skin protection, however, is necessary in in- dustrial use, because of their rapid skin penetration. The most characteristic biological effect of the chloroanilines is the for- mation of methaemoglobin, but the standards for occupational exposure are based primarily on skin irritation. 28 The USSR standards for drinking-water (0.2 and 0.05 mg/l for p-chloro- aniline and 3,4-dichloroaniline, respectively) are based on organoleptic proper- ties. Existing concentrations are well below these levels and therefore give no cause for concern. CTILOROPIIENOLS The chlorophenols evaluated are either used directly as pesticides or as intermediates in their manufacture. Most of the experience of toxicological effects in humans has been derived from accidental contamination of the skin during occupational exposure, and also from inhalation ofhigh concentrations under similar circumstances. Ingestion in food or drinking-water, however, is much more likely to be the major cause of exposure of the general population. In addition to their origin in industrial waste, the di- and trichlorophenols also arise from both environmental and metabolic degradation of herbicides and from tlte ctrlor- ination of water supplies. Chlorophenols are readily excreted as conjugates, which reduces the possi- bility of their accumulation in tissue; pentactrlorophenol is excreted much more slowly than the other compounds in the group, especially in children. In spite of their appreciable volatility and the sensitive analytical methods available, chlorophenols have not been detected in ambient air. This confirms that atmospheric contamination poses no general risks. An acceptable concentration for drinking-water of 0.5 pg/l has been recommended by the US Environmental Protection Agency on the basis of taste. In the absence of positive indications of mutagenicity and carcino- genicity, there is no need for other criteria to be used. 2,4, S-Trichlorophenol The compound is the major intermediate for the herbicide 2,4,5-T;it is of moderate volatility and water solubility, with a low taste and odour threshold. Its lipophilicity varies with pH, which affects the degree of ionization and salt formation. It is frequently observed in surface water, but at levels that would result in a daily intake much below the ADI, calculated on the basis of sub- acute studies on the cat. In the absence of data on mutagenicity or carcinogenicity, there is no reason to consider criteria other than taste for drinking-water quality limits. The US En- vironmental Protection Agency has proposed a limit of lOpgll, based on taste. 2, 4, 6-Trichloro pheno I This isomer, which is produced by chlorination of water and is a major metabolte of lindane, has apparently shown carcinogenic activity in recent animal studies, but no details are available as yet. 29 Pentachlorophenol The compound is extensively used as a wood preservative and, in tropical countries, as a molluscicide. It is regularly found in surface water and has been reported in sea-water and in aquatic and terrestrial wildlife. Subacute and chronic animal toxicological data are surprisingly deficient for a compound that has a history of acute human poisoning incidents. Such data as are available are difficult to interpret because of the presence of vari- able proportions of impurities in the samples tested. They have, however, been used by the US Environmental Protection Agency to compute an ADI of 3pg.kg-'.d-r. On the basis of this, a maximum concentration of l40pg/l in drinking-water supplies has been recommended. Levels observed to date in wildlife do not at present give cause for con- cern, but the highest could be sufficiently close to the ADI to warrant more extensive monitoring. The occupational environment has been recognized as a potential source of hazard to workers. Permissible exposure limits for this environment range from 0.1 mg/m3 (USSR) to 0.5 mg/m3 (uSA). The paucity of data on the carcinogenicity of pentachlorophenol led the group to recommend that adequate testing be undertaken. It is also recom- mended that epidemiological surveys of workers exposed to the chemical be carried out. 30 IV PRACTICAL ASPECTS OF POLLUTION MONITORING AND CONTROL AN ALYTICAL DETT.]RMINATION Much of the present concern about environmental health hazards arises from the discovery of low concentrations of certain man-made compounds widely distributed in the environment. It can be argued that the very large number of reported analyses of chlorinated pesticides and polyctrlorinated biphenyls is due to the fact that such chemicals are relatively easy to identify and quantify at low levels using gas chromatogaphy (GC) with electron capture detector. Many other compounds, however, which may be present at much higher concentrations, are more difficult to detect and so have not be- come subjects for extensive international discussion. Almost all of the chloro-aromatic compounds discused by the group can be determined by GC, but with widely differing sensitivities. There is a par- ticular need to improve methods of analysis for halo-aromatic compounds other than chloro derivatives. The required limit of detection of such methods should be of the order of l0 pAll. The growing use of mass spectrometry (MS) in recent years may well change this pattern and the US Environmental Protec- tion Agency now regards the GC/MS combination as the standard method for residue determinations. In general, limits of detection for chemicals in water and air samples are about 1000 times better than for tissues and sediments, since a solvent ex- traction stage with a small volume of solvent may be used for the former, whereas with tissu:s much larger volumes of solvent are necessary and more lipophilic contaminants are extracted. For routine monitoring of organic pollutants, indirect indices such as chemical oxygen demand, biochemical oxygen demand, total organic carbon, and total organic chlorine are of value. However, these are not sufficient when specific information is required about the presence of particular pollutant com' pounds. When an episode of chemical pollution is first recognized - perhaps by altered smell or taste of the watera - information on the nature of the 4 For some chemicals, the organoleptic properties are such that contaminated water would be undrinkable at pollutant concentrations well below those that might cause ad- verse effects on health. For many others, however, detection in water by taste or smell is possible only at concentrations that could prove hazardous to health. 3l pollutants is frequently lacking. For preliminary investigations, therefore, it is more appropriate to use analytical methods suitable for groupsor classes of chem- icals, e.g., UV or IR spectrometry. More sophisticated techniques such as GC, particularly in conjunction with I,tS, may then be used to determine the precise identity of the pollutants. This combination of techniques, however, is not suitable for routine analysis nor, at present, for quantitative analysis. Other sophisticated techniques such as high-pressure liquid chromatography, combined in some cases with spectrometry and element-specific detectors, are likely in future to be of value in identifying pollutants. WATER TREATMENT A variety of water treatment processes can be used to remove halogenated benzenes, phenols and toluenes from drinking-water. Aeration Aeration can remove volatile organic compounds. Experience in the Netherlands (Brinkmann, personal communication) indicates that aeration will remove about SWo of mono-, di-, and trichlorobenzenes and mono- chlorotoluenes. Sand lih rat ion f bank fil t rat io n Little information is available on the efficiency of slow sand filtration in reducing the content of chlorinated benzenes, chlorinated anilines, and chlorinated nitrobenzenes in water. Some measurements show a decrease in concentration of such materials following burk filtration. The removal efficiency of this process has been reported to be 40% for aniline, 2V, for p-chlo roanilin e, ar,d 5 Vo for 3,4-dichloroaniline . A c tiv ated carbo n lilt ration Removal of halogenated aromatic compounds can be achieved by activated carbon filtration. Data from the Netherlands (Table 5) indicate removal ef- ficiency as high as 9Vo. However, very low filter efficiencies (10-507a) have also been recorded. This could be due to filter exhaustion and to difficulties in measuring concentrations near detection limits (0.005 pg/l). A study of the removal of organochlorine compounds by a variety of activated carbon filters has shown great differences in adsorption capacity, depending on the nature of the filter and individual pollutants. Differences of more than SVo in removal efficiency have been observed. When treating water containing halogenated aromatic benzenes, toluenes, and phenols, it may therefore be necessary not only to choose the most suitable type of carbon, but also to combine different types of carbon in the filtration system. 32 Table 5. Removal efficiency of activated carbon filtration in two water treat- ment plants in the Netherlands Compound Removal$l Concentration(wltl Data bad on 5-10 amples monochlorobenzene p-dichloroben zene o-dichloroben zene rndichlorobenzene trich lorobenzene p-chlorotoluene o-chlorotoluene 70 90 90 75 90 50 75 0.02-0.10 0.20-0.40 0.80-2.00 0.04-0.10 0.07-0.13 0.01-0.03 o.o2-o.25 Data bad on I ample aniline p-chloroaniline 3,4-dichloroaniline o,o,q-trif luoro4- aminotoluene 95 70 95 90 1.0 0.1 0.3 0.1 METHODS OF SOIL AND GROUNDWATER POLLUTION MONITORING AND CONTROL Soil and groundwater constitute an ecosystem with a rather long response time to pollution, and therefore responsible authorities and their advisers generally have a sufficient interval to decide on the nature and scope of inter- vention necessary when pollution is suspected or established. Nevertheless, it is desirable to have a standard procedure of intervention available for instances of chemical pollution. A model procedure being applied to pollution monitoring and control in Denmark, and which could be applied elsewhere, is described in Annex 2. This procedure comprises three consecutive stages: preliminary exam' ination, investigation, and surveillance. The aim of the first stage is to make a rapid assessment of possible hazards to human health and the environ' ment in terms of acute and long-term effects. During the second stage, the need for decisions on prevention and control measures is analysed. This stage includes field and laboratory activities. Finally, the third stage is directed JJ towards implementation of the agreed measures and asessment of their ef- fectiveness; it may also include revision of the original risk assessments, as necessary. Depending on the nature of a particular incident the model system pre- sented can, of course, be suitably modified. The important requirement, however, is to have such a procedure available when an episode of pollution actually occurs. 34 vCONCLUSIONS AND RECOMMENDATIONS GROUNDWATER POLLUTION IN VICENZA PROVINCE l. The group endorsed the decision of the Veneto Regional Government to terminate the use of contaminated groundwater for public supply. 2. Owing to the paucity of basic toxicological data on halogenated toluenes present in the contaminated groundwater, the group lacked a scientific basis on *hich to recommend acceptable levels of these chemicals in water or body tissues. It was therefore recommended that the restriction of public con- sumption of the contaminated water should continue until adequate data are available for a definitive assessment. 3. It was noted that contaminated water continues to be used for irrigation and, in some areas, for consumption by farm animals. While no meaningful information was available on fluorotoluene concentrations in tissues resulting from the use of this water, a concentration of l0 pg/l of these substances was tentatively recommended as acceptable for such purposes. It should be recog- nized, however, that this recommendation represented the considered opinion of the group rather than the statement of a scientifically determined "safe" limit. 4. To facilitate risk assessment when further toxicological data are available' the levels of the h.logenated toluenes and their substitution products should be monitored in milk as well as in tisues of farm animals' 5. If the use of groundwater is found to be affectingthe quality of products in agriculture or the efficiency of waste treatment plants in industry, a compre' heniive monitoring programme should be implemented and action taken as necessary. 6. Since the groundwater is likely to remain polluted for many years, it was recommended that systematic monitoring be maintained to allow continuing study of the concentration of the compounds. Such study will provide data on overall changes in concentrations and on such factors as differential leaking, absorption or degradation, and diffusion to ground layers. The results obtained should be assessed periodicallY. 35 7. A definitive assessment of the environmental pollution episode and an evaluation of the health hazards to man will be possible only when adequate toxicological data are available. It was therefore recommended that further extensive research programmes be implemented as a matter of urgency. GENERAL l. It was agreed that a mechanism should be established by the WHO Re- gional Oflice for Europe whereby, following incidents involving the accidental release of potentially toxic chemicals to the environment, or in anticipation of the possibility of such release, ad hoc groups of international experts could be brought together to provide guidance on public health and environmental risks. 2. The initiative of the Veneto Regional Government in requesting WHO to convene a working group to review the toxicity of particular groupsof chemi- cals, following the recent case of groundwater pollution, had provided a useful precedent for holding such meetings. 3. It must be accepted that, as in the present case, incomplete data and in- sufficient time will be available for exhaustive reviews by the working groups, but it is essential in emergencies to provide firm guidance on the nature and extent of likely hazards, if necessary by extrapolation or intuitive interpreta- tion of limited information. 4. The composition of the working groups must ensure the availability of expert knowledge of the particular groups of substances, with reference to their chemistry, modes of production, disposal, likely distribution in the en- vironment, and toxicolory. 5. As it will sometimes be necessary to organize the working groups at very short notice, each participant should be asked by WHO to bring as much rele- vant data as possible to the meeting. The WHO secretariat should be in a posi- tion to assemble other data, either througfr the International Register of Potentially Toxic Chemicals or directly from a wide range of contacts. 6. It should be recognized that, in an industrialized society producing and using an increasingly wide range of chemicals, releases of materials which could pose a risk to public health and to the environment will sometimes occur. While the primary responsibility for protection rests with industry,contingency plans strould be made by the appropriate authorities to deal with these inci- dents in such a way as to minimize adverse effects. 7. The underlying philosophy, however, must be to prevent the occurrence of such incidents. To ensure effective control, the following points should be borne in mind. 36 (a) Systematic environmental impact assessment should be carried out be- fore decisions are made regarding the siting and desigrr of chemical plants and the establishment of safeguards in the prevention of occupational risks and the control of liquid and gaseous emissions and solid wastes. (D) Control measures should take into account the nature of rawmaterials, intermediates, final products, and wastes. Risks during transportation by vehicle or pipeline should also be assessed and minimized. (c) Special risks are associated with the storage of potentially toxic ma- terials close to groundwater used for consumption or irrigation. (d) For effective control, stringent and comprehensive legislation must be enacted, although its practical application may vary according to local environ- mental conditions. (e) Rational decision making in the formulation of control strategies requires the establishment of carefully designed programmes of physical, chemical, and biological monitoring from which trends can be recogtized and needs for action identified. JI REFERENCES l. Belsito, F. et al. Anrwli di chimica, 1979 (in press). 2. Ferrari, G. et al. lReport to the Veneto Regional Authontyl , 1979 . 3. Probst, G.1{. et al. Journal of agricultural and Iood chemistry, 15:592 (1e67). 4. 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Fomenko, W.N. Gigtena i vnitaija,l l: 9 (1965). 55. Cam, C. & Nigogosyan, GJ -lourrwl of the American Medical Association, 183: 88 (1e63). 56. Ocker, R.K. & Schmid, T.Nature,l89:499 (1961). 57. Kondrashova, V. Gigiena truda t professbnali'nye zabolevaniia, 13: 29 (le6e). 58. Scott, AJ. & Eccleston, E. Proceedings of the European Soctety for Srudy of Drug Toxicity,8: 195 (1966). 59. Kiese, M. & Renner, G. Naunyn,Schmiedebergs Archiv fi)r expeimentelle Pa tholo gie u nd Pharmakolo gie, 246 : I 63 ( I 963). 60. Lehman, K.B. Archiv ftir Hygiene und Bakteriologie, ll0: l2 (1933). 6 I . Triosi, F .M. Medicina del lavoro, 53: 128 (1962). 62. Scotti, P. & Tomasini,H. Medicina del hvoro, 57: 662 (1966). 63. Patty, F.A. Industial hygiene and toxicologt lnterscience Publishers, 1963, Vol. 11,p.1402. 64. Kobayashi, S. et al. Tokoku medical ioumal, 19 356 (1972). 65. Stevens, M. Bitish ioumal of industrial medicine,24: 189 (1967). 66. IARC monographs on the evalwtion of the carcinogenic risk of chemicals to mtn: Halogerwted hydrocarbons. Lyons, International Agency for Re- search on Cancer, 1979 (IARC Monographs, Vol. 20). 67. Deichmann, W. et al. Joumal of pharmacologt and expeimental thero' peutics, 7 6: 104 (1942). 68. Farquaharson, M.E. et al. Bitish i oumal of phumocolo gt,l3 : 20 ( I 95 8). 69. Sdrwetz, B.A. et al. Toxicology and applied pharmacologt, 28: I 5 I (197 4). 70. Vogel, E. & Chandler, J.L. Expeientia,3O'. 621 (1974). 71. Gordon, D.Medical joumal of Australia,43:485 (1956). 72. Menon, l.A. Bitish medical iounal, l : 1 156 (1958). 73. Armstrong, R.W. et al. Journal of pediotics, 7 S: 317 ( I 969). 4l Annex I DESCRIPTION OF THE GROUNDWATER POLLUTION TNCIDENT, VICENZA PROVINCE, ITALY Type of industry The chemical factory involved specializes in the production of fine chemi- cals, the majority of rvhich are fluorinated products. It employs, directly or indirectly, about 500 local people. The main chemical processes used include electrofluorination, chlorination, fluorination, and nitration. The three most important production lines are: - perfluorinated derivatives; - intermediates for pharmaceuticals ; - intermediates for crop protection chemicals. Annual production of these intermediates has risen from 200 t/year n 1973 to the present level of 2500tlyeat. Site of factory The factory is located on the lower part of the Agno River, a short dis- tance from the opening into the Po Valley, in Vicenza kovince, Northern Italy. A small river, the Poscala, flows along the perimeter of the factory and receives the process waste waters after purification. This stream flows into the river Gui, a tributary of the Adige, which in turn flows into the Adriatic Sea. Geological formation in the area In geological terms, the more superficial layers of the area are charac- terized by alluvial sediments of the Quaternary period (pebbles, gravel, and sand) with lens inclusions of fine sediments (silt and clay). The thickness of these layers varies between 70 m and 100 m. The formations below them are of a rock type of the Miocene epoch, the total thickness ranging from 55m to 65 m. The alluvial layer is the water-bearing stratum in these formations and is clearly defined by the hydraulic gradients ofthe surrounding areas. Wells in the area iue, on average, 60-70m deep. The water is used not only by the local farmers but also to supply two public aqueducts. 43 Nature of wastes and discharge procedures Liquid effluent from the factory comprises two major fractions l. Treatment waters from the nitration process which, until 1976, were partially neutralized and then discharged. Their composition was: Fluorides Sulfates Nitrates Chlorides 4{Noroc,o,a-trifl uorotoluene and the 3-nitro and 3,5- dinitro derivatives 4-hydroxy-3,5-dinitro- o,o,o-trifl uorotoluene 4-ctrloro-3,5 dinitrobenzoic acid ^ 100-200mgfl +0.5-l.5gn 2. Waste acids from the nitration processes were formerly diluted and neutralizsd with lime. The resulting sludge was collected in a trench inside the perimeter of the factory, while the liquid fraction was discharged in the same manner as the treatment waters. The waste acids contained l-2Vo of organic compounds of which 8Vo was 4chloro-3,Sdinitrobenzoic acid; the remaining 2Wo was composed of 4+lrloro-3-nitro- and 4chloro-3,S-dinitro- o,c,a -trifl uorotoluenes. Pollution episode During the summer of 1977, it was realized that water from some wells had been polluted by halogenated aromatic compounds, subsequently iden- tified as: 4-chloroc,c,c -trifl uorotoluene, 4+lrloro -3 -nitroc,o,o-trifl uorotoluene, 4-ctrloro-3,5 dinitro-c,o,o-trifl uorotoluene, 3 -nitro+,o,o -trifluorotoluene, trichloroethylene, perchloroethylene. Analyses have since been carried out on samples from hundreds of wells in the area in order to determine the distribution and concentration of pollutants 44 +O.t-0.2e4 40.5-l.0cn 4 1.0-5.0 cn + 1.0-5.0 g/l in the water. Quantitative analyses for the entire area have been restricted to 4-chloro-3-nitro-o,o,o-trifluorotoluene, which was found to be the pollutant present in highest concentration, i.e., from 5 to 800pg[ in well-water. In the wells that supplied water to the aqueducts of Creazzo, Monteviale and Sovizzo, however, the concentration of 4<hloro-3-nitro-o,a,e-trifluorotoluene was found to be lower, typically in the range of 0.5 to 90 pell. Administrative and technical action When pollution by these compounds was recogrized and their sources identified, the local authorities immediately prohibited the use of groundwater for drinking purposes, and new sources of water supply for the aqueducts were arranged. There were, however, no limitations placed on the use of conta- minated water for other purposes such as irrigation or consumption by farm animals. Simultaneously, having established that, for economic reasons, the production of 4-ctrloro-3,5-dinitroo,o,c-trifluorotoluene had ceased at the end of April 1977 the authorities decided that production could be resumed only on condition that effective treatment plants were constructed to ensure proper purification of gaseous and liquid effluents, in both normal and abnormal process conditions. The improvements subsequently introduced in the factory are as fol- lows. l. All reactors are now fitted with expansion chamben to accommodate possible excessive rises in pressure and are connected to tanks in which the reactor contents can be collected. The exhaust gases are treated before being released to the atmosphere. 2. All the plants and surrounding areas have been enclosed in an im- permeable perimeter with raised edges. Possible spills and associated washing water can therefore be drained into a collection tank and then pumped to a liquid effluent incineration plant. This plant, which operates at a working temperature of approximately 1000"C, now also receives the liquid fraction from the acid neutralization process and the nitration treatment waters asso- ciated with the final product (4rhloro-3,5-dinitro<,e,c-trifluorotoluene). 3. The residual waters from "scrubbing" of the exhaust gases are neu- trahzed and then filtered through activated carbon. This filtration system consists of three pairs of filters, two of which work in series while the third is held in reserve. The working capacity of the filters is such as to ensure that, even in the worst case, the concentration of chloro-nitroa-fluorotoluenes will be below 5 prgfl. "Lime" from the neutralization plant is largely in the form of calcium fluoride (approximately 8Vo), but it also contains 0.2-0.5% of organic compounds (mainly 4rhloro<,o,o-trifluorotoluene). This sludge is now col- lected in a special impermeable tank inside the factory. 45 Monitoring programme The nature of the pollutants and the very low levels achieved by the purification plants (less than 5 pgfl) are such that continuous, automatic monitoring of the discharges is not feasible. The analyses are thus performed twice a day on samples collected between the first and second filter of each pair. As soon as the analytical results show that the adsorption capacity ofthe carbon is being reached (chloro-nitroa-fluorotoluenes)2Opgfi) the first pair of filters is disconnected and sent for regeneration, and the reserve pair con- nected. For monitoring in the polluted area (outside the factory perimeter), a network of sampling points has been established, based on hydrogeolog- ical parameters, in order that, by regular analyses, the concentration of 4- chloro-3-nitro<,a,o-trifluorotoluene can be followed as a function of time. In July-August 1979 the concentrations measured were in the range of 0.5 to 2oo1qlt. Other studies undertaken Studies carried out as a consequence of the pollution incident include: (a) studies on the behaviour of the pollutants in soil; (D) studies on the transfer of the compounds to plants; (c) some preliminary toxicological studies on the compounds; and (d) epidemiological studies on factory workers and on the population living in the polluted area. Although the studies are still in progress, some preliminary results are available (see chapters I-III ofthe report). For the past 2 years, the factory workers have been given haemotological and clinical examinations at 6-monthly intervals; no significant effects have been observed to date. During this period, they have been exposed to atmos- pheric halotoluene concentrations of (l mg/m3. Epidemiological studies were made on random samples of the population living in the area of pollution and on a reference sample of people living outside the area. The former population was classified in terms of the water supply available to the family, i.e., houses with wells only, houses with a water supply from both wells and the aqueduct, and houses with a supply only from the aqueduct. The feeding habits of the people were also studied to assess the amount of water drunk and the quantity used for cooking. At the same time, an epidemiological cross-sectional morbidity analysis was carried out. No sigtificant differences have been found between the two groups. The studies showed that only a limited portion of the population had pre- viously used the well-water for drinking purposes; both families with access 46 only to weu-water and those served by the aqueduct normally used bottled mineral water for drinking. This practice had nothing to do with the present episode of pollution. For this reason, and in view of the fact that the odour and colour of water are unpleasant when 4-chloro-3-nitro-o,c,c-trifluorotoluene is present in con- centrations of 5Opgfl or less, it is concluded that the risk to the population from drinking contaminated water, before its use was forbidden, must have been very low. The data from the epidemiological cross-sectional analysis, however, will be useful in the event of a possible future follow-up study. 47 Annex 2 METHODS OF SOIL AND GROUNDWATER POLLUTION MONITORING AND CONTROL Procedure The investigation model described below was developed and is used in Denmark; it is derived from a number of recent chemical pollution incidents involving phenols and pesticides disposed of in the ground. Since there isevery probability that similar incidents will take place in the future, it is most de- sirable that the investigations carried out either by the relevant authorities or directly by the owner of the property on which an incident has or is expected to have taken place should follow a standard procedure. Investigation stages It is generally most convenient to carry out the investigation in stages, such as: Stage l. Preliminary examination Stage 2. Investigation Stage 3. Surveillance Common features of the three stages are described below. It should be noted, however, that each case has its own characteristics, which means that some of the features may be excluded and/or additional points taken into con- sideration. Thus, in some cases it is evident that measures should be taken immediately to plug the source of pollution before initiating action in accord- ance with Stage l. Examples are oil tank leakages, where the tank should be emptied immediately, or broken or leaking transport pipes, where the first action should be to seal the leakage. Preliminary examination (Stage l) Objective: - to provide, as quickly as possible, a basis on which to assess whether there is any acute danger to health or the environment. The following information should be obtained: l. Data on the polluting substance(s): - chemical composition - quantity 49 - packaging - dumping place - dumping period. Sources: manufacturer (or other reliable and relevant source). 2. Local hydrogeological conditions (possibly pathways of the polluting substance): - soil conditions - groundwaterconditions - surface receiving waters - water abstraction conditions. Sources: regional water plans, drilling archives, regional and local water supply data, etc. 3. Environmental impact (effect of the substance): - toxicity - other environmental hazards. Sources: manufacturer and environmental authorities; othen with expert knowledge. The following measures should be taken: Recognition: careful inspection of the pollution area. Action following the inspection: - preparing notes - taking photographs - collating knowledge of the local area - delimiting the hazard area, if necessary - restricting access to the area, if necessary - taking samples, if necessary. Estimation: at this stage, the preliminary, rough assessments of acute orlong- term risks, which may often be made on the basis of available information. The preliminary investigation should be made as quickly as possible, and, if possible, the results should be available within five days. Since the question of responsibility often cannot be considered before Stage I is initiated, to facilitate rapid action the relevant authority (local, regional, or national, i.e., environmental protection agency) may have to give an economic guarantee for the implementation of the stage. On the other hand, it is important not to act in panic and thereby increase the pollution hazards. Typical examples of such action and its consequences are: (a) stopping the use of polluted wells - the pollution might spread to neighbouring wells (the water should instead be abstracted constantly and be discharged in an appropriate manner); (b) drilling of wells - the protective clay layers might be perforated; (c) excavating - the surface water and air might be polluted. s0 Stage I activities should be carried out by bodies with sufficient expert knowledge (institutions, universities, authorities) and should be coordinated by the authority that initiated the investigation. The sequence of events is shown in Fig. I . Preliminary investigation Collection of information on - the polluting substance - hydrogeology - impact (Stage 1 ) Recognition Estimation Assessment of the acute risks to health and the environment Acute risks (possi bl Long-term risks No risks Reporting Stop Decisions to: - stop the pollution source - excavate - pump away - stop water abstraction - issue warnings I nvestigation (Stage 2) Fig. 1. Sequence of events in Stage 1 51 Investigation (Stage 2) Ob jectives: - to procure the necessary knowledge of the behaviour of the polluting substance and its properties in soil, and to assess the degradation processes that will take place; - to obtain the necessary knowledge of the hydrogeological conditions near the pollution area, and to describe the groundwater movements with reasonable accuracy; - to obtain the necessary knowledge of the environmental hazards of the substance. Res.tlt: The risks are analysed to determine whether the impact on the environ- ment will be unacceptable (pollution of surface and groundwater, effects on biota). The analysis should form the basis on which the authorities make their decisions concerning prevention and control measures (for instance, orden and prohibitions). Action at the start of Stage 2: - establishment of a steering committee - appointment of a project manager - preparation of the investigation programme (economic estimates). Stage 2 components Field activities to delimit the polluted area and to supplement the knowledge of hydrogeological conditions : - test diggng of the assumed dumping area, taking soil and water samples - drilling to register soil stratification (water and soil samples) - sounding - test pumping of wells - borehole logging. Laboratory activities: - analyses ofthe substance - analyses of water samples - analyses of soil samples. Documentstion: - if required, verification and supplementation of data collected during Stage l. Evaluation: - risk analysis. Steering committee. Normally, the activities of the investigation stage in- volve several disciplines. To coordinate these activities, the steering committee should comprise intemal experts of the authorities involved and the polluter and, possibly, extemal experts. The investigation should be led by a project manager. 52 lnvestigation (Stage 2) Field activities Analyses Documentation Risk analyses Prevention measures Prohibition orders Control measures Measures con- cerning source of pollution R E P o R T Surveillance (Stage 3) Monitoring of: - groundwater movements - groundwater quality - surface water quality - water supply plants Checking or revision of risk analyses Correction, if required, of prevention and control measures Fiq. 2. Sequence of events in Stages 2 and 3. 53 The investigation period varies according to individual cases, but normally 3 -6 months are required for the operation, including reporting. Surveillance (Stage 3) Objective: - to monitor the effectiveness of the measures taken and, if necessary, to revise the risk analyses. Stage 3 components: - monitoring of pollution source - monitoring of groundwater movements - monitoring of groundwater quality in neighbouring drinking-water wells - monitoring of surface water quality. The Stage 3 activities depend on the local conditions and cannot be decided on before Stage 2 is completed. They are normally carried out by the local authorities with the assistance of local or specialized laboratories. Current assessments should be made to decide whether the monitoring results call for modification of the prevention and control measures. These assessments should be made with the assistance of the steering committee set up in Stage 2. The sequence of events of stages 2 and 3 is shown in Fig. 2. 54 Annex 3 LIST OF WORKING PAPERS Gambaretto, G. et al. (Institute of Industrial Chemistry, University of Padua, Italy\. Hatogen deivatives of benzene, phenol and tofuene (ICP/RCE 90416). Pearson, C.R. (ICI Brixham l.aboratory, Brixham, Devon, United Kingdom). Halogenated benzenes, anilines and phenols: production, pruperties, dis- tibution and biological effecx (ICP/RCE 90/'l8). Silano, V. et al. (Biochemical Toxicology Unit, Istituto Superiore di Sanitl, Rome, ltaly). Halogenated toluenes ond their nitro and amino derivatives (rcP/RCE eO4l7). 55 Annex 4 LIST OF PARTICIPANTS Temporary advisers Dr F.J.J. Brinkmann, Chemistry and Biolory Division, National Institute for Water Supply, lridschendam, Netherlands Dr D. Djuric, Institute of Occupational and Radiological Health, Belgrade, Yugoslavia Ms J. Fonlund, Directorate for the Environment, National Agency of Environ- mental Protection, Ministry of the Environment, Copenhagen, Denmark Professor G. Gambaretto, Director, Institute of Industrial Chemistry, University ofPadua, Italy Professor F. Kaloyanova, Director, Institute of Hygiene and Occupational Health, Sofia, Bulgaria Professor W. Koransky, Institute of Toxicology and Pharmacolory, University of Marburg, Federal Republic of Germany Dr B. Paccagrella, Director, lnstitute of Hygiene, University of Padua, Italy (Chairman) Mr C.R. Pearson, Brixham laboratory, Brixham, United Kingdom Dr D. Rondia, Associate Professor, Laboratory of Toxicology, University of Lidge, Belgium Dr L. Rosival, Director, Centre of Hygiene, Research Institute of Preventive Medicine, Bratislava, Czechoslovaki a (V ice thairman) Dr C.M. Schiller, National Institute of Environmental Health Services, Research Triangle Park, NC, USA Dr V. Silano, Director, Department of Biochemical Toxicology, laboratory of Toxicolory, Istituto Superiore di Sanith, Rome, Italy Dr S. Tarkowski, Head, Division of Industrial Toxicolory, Institute of Occup- tional Medicin e, Lodz, Poland (Rapporteur) Representatives of other organizations Intemational Agency for Research on Cancer (IARC) Dr L. Tomatis,a IARC, Lyons, France a Participation expenses not paid by WHO. 57 National observers Mr S. Barbasetti di Prun,a Director, Public Relations Service, Veneto Regional Government, Venice, Italy Dr P. Bonifaci,a Public Health Officer, Province of Vicenza, Vicenza, Italy Dr E. Carli,a Head, Public Health [aboratory, Vicenza, Italy Dr E. Cosma,a Department of the Environment, Veneto Regional Government, Venice, Italy Dr C. Favaretti,a Institute of Hygiene, University of Padua, Italy Professor L. Giannico,a DirectorCeneral, Ministry of Health, Rome, Italy Assessore F. Guidolin,a Veneto Regional Government, Venice, Italy Professor G. 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