Some factors affecting the distribution and rate of action of insecticides

Bull. Org. mond. Sante 11971, 44, 221-224Bull. Wld Hlth Org. Some Factors Affecting the Distribution and Rate of Action of Insecticides A. B. HADAWAY 1 The amount of insecticide that reaches a critical site ofaction within an insect is affected by a number of physical and chemical processes both within and outside the insect. This paper reviews some of these processes, with particular attention to those external to the insect, whose action commences at the moment an insecticide is released into the environ- ment. On the basis of research that has been conducted on such processes, conclusions are drawn as to the properties that are desirable, from the point ofview ofinsecticidal efficiency, in new compounds. To fulfil its function as an insecticide, a chemical released into the environment must first reach the target insect, then pass through the chemically com- plex natural barrier of the integument, and finally arrive in sufficient concentration-either in un- altered form or as an active derivative-at a critical site of action. During this journey various physical and chemical processes progressively reduce the amount that passes from one stage to the next, until only a minute fraction of the dose reaches the site of action and is responsible for the biological response. Ideally we should know what factors determine the progress of a compound through the different stages. Unfortunately these processes become more difficult to study, and hence our knowledge of them decreases, as the distance from the point of release of the compound increases. Thus, after many years of intensive research the site of action of a compound may not be known with certainty, although in most cases it is generally considered to be in the central nervous system. Again, surprisingly little is known about the route taken by an insecticide from the integument to the site of action. The general assumption has been that it passes through the integument into the haemolymph, in which it circu- lates to the central nervous system and other body tissues. LeRoux & Morrison (1954) concluded from the topical application of '4C-labelled DDT to houseflies that the blood appears to transport but not to accumulate the activity, since the radioactivity in 1 Director, Tropical Pesticides Research Unit, Porton Down, Salisbury, England. the haemolymph amounted to only 1% of the total recovery. There is, in fact, little quantitative evidence of the passage of insecticide from the cuticle into the haemolymph. Matsumura (1963) found that malathion topically applied to adult Periplaneta americana is selectively absorbed in the initial stage by the cuticle, and studies by Lewis (1965) indicated that DDT very rapidly saturates the epicuticular wax layer of adult blowflies (Phormia terraenovae) but does not diffuse very freely into the haemolymph. Burt & Lord (1968), however, showed that the haemolymph of Periplaneta americana can carry relatively large quantities of the moderately water- soluble compound diazoxon. This concept of the movement of insecticides from the integument in the haemolymph has been chal- lenged by Gerolt (1965, 1969, 1970), who has pro- duced evidence suggesting that dieldrin and the more water-soluble oxime carbamates migrate laterally in the integument and reach the central nervous system by way of its rich supply of tracheae. Whatever the route taken, however, there is no doubt that within the insect a chemical is exposed to the action of a number of enzymes and biochemical processes, resulting in its conversion to an active derivative or in its degradation and excretion. Only very limited quantitative data are available on the rates at which insecticides penetrate the integument of the insect, and on the factors that affect these rates. This is particularly true for prac- tical formulations of insecticides. The Tropical Pesticides Research Units have for many years been concerned with the efficient, economic, and safe use 2630 - 221- A. B. HADAWAY of insecticides in developing countries in tropical areas and have accordingly conducted research on the factors affecting events that take place largely outside the insect-i.e., those that occur from the moment an insecticide is released until it is taken up by the cuticle. Our work thus has a practical bias, but it has indicated some of the properties that are desirable in new insecticides. Starting at the one extreme, the point of release into the environment, considerable information has been accumulated on the factors determining the distribution and deposition of insecticide sprays. Earlier research on the production and behaviour of spray drops of different sizes, carried out in con- nexion with the control of tsetse and locusts by aerial spraying, paved the way for the equipment and techniques now used in the ultra-low-volume application of insecticides for area treatment against adult mosquitos and for crop protection (Yeo, 1960; Sayer, 1959; reviewed byHadaway& Johnstone, 1969). Vector control, however, depends less on the direct impaction of insecticides on insects than on their uptake by the insects from deposits in build- ings, on clothing, or on vegetation. Although the direct topical application of compounds in solution to the integument can provide valuable information on some aspects of insecticidal activity, it omits the vital stage of movement from a deposit to the cuticle. Olson & O'Brien (1963) found that the degree to which six solutes penetrated the cuticle of the cockroach (entry through the epicuticular lipid being gained via a small volume of organic solvent) was proportional to the extent to which they entered an aqueous phase. Our studies with adult mosquitos indicate that limiting factors in the uptake of insecti- cides from deposits can include their solubility in lipids as well as their partition characteristics. The proportion of the dosage applied to a material that remains at the surface available for contact with insects is related to the physical properties of the insecticide and its formulation and of the material to which it is applied. Insecticides in the form of emulsions or solutions often penetrate the substrate to a greater extent than those in the form of suspen- sions of solid particles, which can be filtered off at the surface, and for general purposes water-disper- sible powder formulations are preferred to emulsions and solutions. If the active ingredient of a water- dispersible powder is a liquid, however, then on dispersion in water a considerable proportion may be displaced from the inert carrier and form an emulsion that penetrates porous substrates. Insecticides can diffuse from deposits of water- dispersible powders to the integument of insects where the two are in contact, and the duration of contact required to produce a given biological res- ponse is a measure of the rate of entry of insecticide. The same response may be obtained after a shorter contact time if the insect can pick up particles of insecticide and retain them so that diffusion continues after the insect has left the deposit. Two of our standard test materials provide an illustration. On plywood, which is relatively impermeable, the wetting and dispersing agents remain on the surface, where they evaporate, causing the insecticide particles to adhere to one another and to the surface of the substrate. On plaster, however, which is porous, the particles are filtered off at the surface and are readily available for pick-up. The great differences in effectiveness that can be obtained are shown by the results (Table 1) obtained with water-dispersible Table 1 Contact toxicity to An. stephensi of OMS-1 268 and OMS-1269 * Average mortality (%) 24 h after Material exposures of the followingCompound sprayed duration (min) 2 5 30 60 OMS-1268 plywood 31 96 plaster 0 4 OMS-1 269 plywood 0 0 plaster 86 100 * Deposits formed from water-dispersible-powder formulations, at 1 g/m2. powders of the two geometric isomers of the 2,6-dichlorophenylglyoxylonitrile oxime O-ester with 0,0-diethyl phosphorothioate. One of these, OMS- 1268, is a liquid whose LD50 for Anopheles stephensi is 5 ng per female; the other, OMS-1269, is a solid having melting point 61-62°C, whose LD50 for An. stephensi is 14 ng per female. The pick-up of particles from deposits can be influenced by various other factors, including tarsal morphology, movement of the insect, and the phy- sical state of the deposit. Lewis & Hughes (1957) showed that dry particles of a lipid-soluble substance adhere more strongly to the cuticle of adult blow- flies than do dry particles of a substance insoluble in 222 FACTORS AFFECTING THE DISTRIBUTION AND RATE OF ACTION OF INSECTICIDES 223 Table 2 Action of propoxur and OMS-1094 on An. stephensi % KD 15 min after topical application Solubility Partition LD5o of the following amounts (ng per female mosquito)A Compound inLn-hexane a coefficient, (ng per female in solution n-hexane/water mosquito) __ |_2.0_ |_ 2.5_|_ 3.2 1.5 2.0 2.5 3.2 propoxur 0.18 0.72 2 25 65 75 90 OMS-1094 0.025 0.26 2 25 40 60 100 Mortality (%) 24 h after contact of the following duration (min) Time to first flight Time to 50 % KD with wdp b deposits on plywood (min) (min) Compound 2 5 15 30 upon continuous exposure to wdpb deposits on plywood propoxur 79 100 3 7.2 OMS-1094 0 21 100 12 21.5 a % w/v saturated solution at 25°C. b Water-dispersible powder. lipids. Hadaway & Barlow (1951) found an optimum particle size of 10-20 ,um for contact toxicity ofDDT and methoxychlor to adult mosquitos, and Hadaway, Barlow & Turner (1970) showed that particle size has less effect on the contact activity of the more toxic compounds dieldrin, gamma-HCH, iodofen- phos, chlorphoxim, and Mobam.t Comparative studies of the rates of action and toxicities of closely related carbamates and organo- phosphorus compounds from solutions applied topically and from dry deposits of water-dispersible- powder formulations indicated that the diffusion of an insecticide from a deposit into adult mosquitos is related to its solubility in a lipid model, n-hexane, and to the partition coefficient between this solvent and water (Hadaway & Barlow, 1966a; Hadaway et al., 1970). Very low solubility is a limiting factor in the uptake of a solid insecticide and is associated with a slow rate of penetration and low contact toxicity. When the solubility is high enough to ensure solu- tion in the wax layer of the cuticle, penetration and contact activity are favoured by a low value for the partition coefficient. The results obtained with propoxur and the closely related carbamate 2,3-dihydro-2-methylfuran-7-yl methylcarbamate (OMS-1094) are used as an illustration. The two compounds are highly (and equally) toxic to adult Anopheles stephensi and they have a similar fast rate of action after topical tProprietary names against which this symbol appears are identified in the Glossary on pages 445-446. application in solution. However, the solubility of OMS-1094 in n-hexane is lower than that of pro- poxur, and it has a slower rate of action and a lower contact activity from dry water-dispersible-powder deposits on plywood (Table 2). Lipid-solubility also appears to be a limiting factor in the uptake by tsetse flies (Glossina austeni) of three closely-related vinyl phosphates from water- dispersible-powder deposits on plywood (Table 3). The three compounds are approximately equally toxic when topically applied in solution, the LD50 values being 15-20 ng per fly, but their contact toxicity decreases with decreasing solubility in n-hexane. Compounds with more favourable physical pro- perties can be produced by alterations in molecular structure, and from this point of view N-acylation of the carbamoyl portion of aryl methylcarbamates is of interest. The N-acyl derivatives may show reduced toxicity to mammals with little or no loss of intrinsic insecticidal activity but with enhanced con- tact toxicity resulting from more favourable solu- bility and partition properties. Variations in mole- cular structure, however, are accompanied by changes in intermolecular forces, which control not only these properties but also others, such as melting point and volatility. N-acylation is in fact often accompanied by a great increase in volatility and the resulting derivatives frequently lack the persistence required for residual insecticidal activity (Hadaway & Barlow, 1966b; Hadaway et al., 1970; Barlow & Hadaway, 1970). 16 224 A. B. HADAWAY Table 3 Contact toxicity of three vinyl phosphates to G. austeni * Mortality (%) 48 h after Solubility in exposures of the followingCompound n-hexanea duration (min) 1 5 15 30 OMS-712 b 1.05 100 29 91 OMS-595 c 0.43 18 72 0 20 OMS-711 d 0.18 0 0 *The deposits were formed from water-dispersible-powder formulations, at 1 g/m' on plywood. a % w/v saturated solution at 25°C. b 2-chloro-1 - (2,4-dichlorophenyl)vinyl dimethyl phosphate. C 2-chloro-1 -(2,4,5-trichlorophenyl)vinyl dimethyl phosphate. d 2-chloro-1 - (2,5-dichlorophenyl)vinyl dimethyl phosphate. However, three carbamates-carbaryl, Landrin,t and Mobam f-are sufficiently nonvolatile that the sacrifice of some degree of persistence could be tolerated. N-acyl derivatives of these compounds were therefore synthesized and were found to be persistent; moreover, the N-acetyl derivatives are better contact insecticides than the corresponding parent carbamates. The contact toxicity of the N-propionyl and N-butyryl derivatives is inferior to that of the corresponding N-acetyl compound, and the increase in lipid-solubility appears to be more than counterbalanced by the increase in partition coef- ficient between lipid and water (Hadaway et al., 1970). Thus, although these N-acetyl derivatives are not better contact insecticides than several other carba- mates, their performance supports previous indica- tions that lipid-solubility and partition characteristics have considerable influence on the uptake of insecti- cides from deposits. Other factors must be im- portant, too, but we can now begin to define the properties required in new compounds from the point of view of insecticidal performance, as follows. (1) A substance that is solid at ambient tempera- tures is preferred as the most versatile material for formulation as solutions, emulsion concentrates, and water-dispersible powders. If a water-dispersible powder is the formulation of choice, then the melting point should be higher than 70°C to facilitate grinding and the formation of a satisfactory product with a high active-ingredient concentration. (2) The substance should be sufficiently soluble in lipids to ensure solution in the epicuticular wax and its partition coefficient between lipid and water should be low, although in fact a compromise be- tween the two properties is usually necessary since they are not independent. (3) The substance should have high intrinsic insecticidal activity and rapidity of action against the vector to be controlled, in order to minimize the effects of poor formulation and any loss of avail- ability by adhesion, sorption, etc. (4) For residual contact activity, the substance should not volatilize to a greater extent than 0.05 g/m2/day from deposits of 1 g/m2 on glass-fibre filters at 25°C. REFERENCES Barlow, F. & Hadaway, A. B. (1970) Pestic. Sci., 1, 117-119 Burt, P. E. & Lord, K. A. (1968) Ent. exp. appl., 11, 55-67 Gerolt, P. (1965) J. econ. Ent., 58, 850-857 Gerolt, P. (1969) J. insect Physiol., 15, 563-580 Gerolt, P. (1970) Pestic. Sci., 1, 209-212 Hadaway, A. B. & Barlow, F. 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