Effects of piperonyl butoxide on exploratory behaviour in female mice.

Previous studies reported that piperonyl butoxide (PBO) induces adverse effects on exploratory behaviour in male mice. However, no consistent effects of PBO treatment were observed in female mice. This study aimed to evaluate PBO's neurobehavioral effects in female mice. Female mice were exposed to PBO through diet to provide levels of 0 (control), 0.025%, 0.1%, and 0.4% from 5 to 12 weeks of age, and selected behavioural parameters were measured. The average female body weight showed no significant effect from PBO treatment through the experimental periods. Regarding multiple-T water maze performance at 10 weeks of age, no significant effect caused by PBO treatment was observed. Exploratory behaviour examination of 8-week-old female mice indicated that the average speed declined in a significant dose-related manner, and the longitudinal pattern indicated a significant difference between the control and high-dose groups. For exploratory behaviour examination at 11 weeks of age, the total exploration distance shortened in a significant dose-related manner, and the average speed declined similarly. These longitudinal patterns showed significant differences between the control and high-dose groups. The PBO dose levels in this study produced several adverse effects on exploratory behaviour in female mice.

Phthirus pubis Infestation of the Scalp: A Case Report and Review of The Literature.

Phthirus pubis usually infests the pubis, groin, buttocks and perianal region. It can sometimes infest the thighs, abdomen, chest, axillae and beard. Eyelashes and eyebrows may be involved in children. The involvement of the scalp is very rare. We describe a case of P. pubis infestation located exclusively on the scalp in an adult woman. Neither lice/nits nor skin lesions were observed elsewhere, including eyebrows, eyelashes, axillae, pubis, buttocks and perianal region (the patient was hairless in the axillae and pubis). A review of the literature is enclosed.

[Scabies of the nail unit in an infant]. / Scabiose de l'appareil unguéal chez un nourrisson.

BACKGROUND: There are no guidelines regarding the management of scabies in infants and recurrence is common at this age. We report the case of an infant with subungual hyperkeratosis and ungual lesions subsequent to classic scabies. PATIENTS AND METHODS: A 7-month-girl, treated 6 weeks earlier with esdepallethrin for scabies, consulted for acquired lesions on 3 toe nails. These nails were thickened and displayed subungual hyperkeratosis. Physical examination of the skin, the finger nails and mucous membranes was otherwise normal. Fungal analyses were negative, but direct microscopic examination revealed numerous larvae of Sarcoptes scabiei as well as ovular debris. The child was treated with urea 40% to obtain chemical avulsion of the nails, and with topical esdepallethrin and a quarter tablet of ivermectin orally; there was no follow-up of the child. DISCUSSION: Ungual scabies has already been reported in crusted scabies and very rarely in classic scabies. Subungual and ungual locations of S. scabiei may constitute a source of reinfestation with scabies in infants. Treatment is not well defined and currently involves chemical avulsion of the nails and the application of topical antiscabies treatment.

Efficacy of pharmacokinetic interactions between piperonyl butoxide and albendazole against gastrointestinal nematodiasis in goats.

To test the hypothesis that modulation of hepatic microsomal sulphoxidation and sulphonation by the cytochrome P450 inhibitor piperonyl butoxide could increase bioavailability of albendazole, the present study was undertaken to understand the pharmacokinetics of albendazole in goats at a dose of 7.5 mg kg- 1 body weight with and without co-administration with piperonyl butoxide at 63.0 mg kg- 1 body weight. Plasma albendazole sulphoxide metabolite, the anthelmintically active moiety, reached its maximum concentration of 0.322 ± 0.045 µg ml- 1 and 0.384 ± 0.013 µg ml- 1 at 18 h and 24 h after administration of albendazole alone and co-administration of albendazole with piperonyl butoxide, respectively. Analysis of the data revealed statistically increased albendazole sulphoxide levels at 24 (P 0.05) in values of maximum concentration (normal and calculated) could be observed between groups of goats. However, values of time to reach the concentration maximum (normal and calculated), area under the concentration-time curve (0-∞ and calculated), minimum residence time, distribution half-life, elimination half-life and total area under the first movement of plasma drug concentration-time curve were significantly higher (P <  0.05) in plasma levels of albendazole sulphoxide in goats following single oral co-administration of albendazole with piperonyl butoxide. The faecal egg count reduction and lower 95% confidence limit for the group treated with albendazole alone were 97 and 68%, while for co-administration of albendazole and piperonyl butoxide the values were 99 and 97%, respectively. The ED50 for egg hatch was 0.196, indicating suspected resistance to benzimidazole anthelmintics. The drug combination proved efficacious against an albendazole-resistant nematode parasite population in goats.

Effects of Maternal Exposure to Piperonyl Butoxide (PBO) on Behavioral Development in F1-Generation Mice.

Female mice were exposed maternally to piperonyl butoxide (PBO) through diet to provide dietary levels of 0% (control), 0.01%, 0.03%, and 0.09% during gestation and lactation periods, and selected reproductive and neurobehavioral parameters were measured in the F1 generation. There was no adverse effect of PBO on litter size, litter weight, or sex ratio at birth. The average body weights of male offspring decreased significantly in dose-related manners on postnatal days (PNDs) 0, 4, 7, and 14 (p = 0.0019, 0.0096, 0.033, and 0.038, respectively) during the lactation period. In female offspring, the average body weights decreased in dose-related manners on PNDs 0, 4, 7, and 14 (p = 0.0027, 0.0104, 0.0193, and 0.0062, respectively). The survival of dams slightly decreased (p = 0.0209) in the high-dose group during the lactation period. With respect to behavioral developmental parameters, surface righting on PND 7 of male and female offspring was delayed significantly in a dose-related manner (p < 0.001 in each). Swimming direction on PND 7 of male offspring was delayed significantly in a dose-related manner (p < 0.01), and for female offspring it was delayed significantly in the high-dose group (p < 0.05). Swimming head angle on PND 7 of male offspring was delayed significantly in a dose-related manner (p < 0.05). Spontaneous behavior examination in males indicated that rearing increased in the high-dose group in the F1 generation. The dose levels of PBO in the present study produced some adverse effects in neurobehavioral parameters in mice.

Subacute oral toxicity of combinations of selected synthetic pyrethroids, piperonyl butoxide, and tetramethrin in rats.

In this study, 70 Wistar rats were randomly divided into seven equal groups (six experimental and one control), which consisted of animals belonging to both sexes. Different combinations of insecticides were administered daily to the experimental groups (group 1: cypermethrin + piperonyl butoxide (PBO); group 2: alphacypermethrin + PBO; group 3: deltamethrin + PBO; group 4: cypermethrin + PBO + tetramethrin; group 5: alphacypermethrin + PBO + tetramethrin; and group 6: deltamethrin + PBO + tetramethrin) for 28 days. During the study period, mortality and serious clinical findings were not observed in any animal. However, feed consumptions decreased in groups 1 and 3 (p < 0.05). Red blood cells, white blood cells, and hemoglobin levels, especially in cypermethrin and alphacypermethrin groups (groups 1, 2, and 4), were found to be higher than the control group (p < 0.05). Furthermore, biochemical changes related to liver, kidney functions, and protein metabolism occurred in males of almost all the groups. Relative liver and kidney weights of the male animals increased in the cypermethrin and alphacypermethrin groups (p < 0.05). The most common finding observed during the histopathological examination of all the experimental groups was centrilobular degeneration in the liver. It was concluded that although clinical symptoms were not observed, synthetic pyrethroid, synergist, and knockdown agent combinations might cause serious abnormalities when administered in certain doses in mammalians.

Evaluation of Three Commercial Backpack Sprayers with Aqualuer® 20-20 Against Caged Adult Aedes Aegypti.

Three commercially available backpack sprayers were evaluated with Aqualuer® 20-20 (20.6% permethrin, active ingredient; 20.6% piperonyl butoxide, technical) against caged adult Aedes aegypti in semifield trials in northeastern Florida. Two battery-powered sprayers, Birchmeier and Hudson, were compared with the standard hand-pump SOLO 425 sprayer, which is currently used in pest management operations. Physical characteristics, droplet analysis, and overall ease of use were documented. Multiple dilutions of the insecticide were also evaluated. The results indicated that the Birchmeier sprayer was the preferable machine in terms of its physical characteristics and operator use. There was no significant difference in percent mortality of the test mosquitoes between the sprayers. Multiple dilutions ranging from 1:9 to 1:1050 of the insecticide resulted in greater than 80% mean mortality.

The importance of modelling the spread of insecticide resistance in a heterogeneous environment: the example of adding synergists to bed nets.

BACKGROUND: Insecticides are an effective and practical tool for reducing malaria transmission but the development of resistance to the insecticides can potentially compromise controls efforts. In this study a mathematical model was developed to explore the effects on mosquito populations of spatial heterogeneous deployment of insecticides. This model was used to identify important parameters in the evolution of insecticide resistance and to examine the contribution of new generation long-lasting insecticidal bed nets, that incorporate a chemical synergist on the roof panel, in delaying insecticide resistance. METHODS: A genetic model was developed to predict changes in mosquito fitness and resistance allele frequency. Parameters describing insecticide selection, fitness cost and the additional use of synergist were incorporated. Uncertainty and sensitivity analysis were performed followed by investigation of the evolution of resistance under scenarios of fully effective or ineffective synergists. RESULTS: The spread of resistance was most sensitive to selection coefficients, fitness cost and dominance coefficients while mean fitness was most affected by baseline fitness levels. Using a synergist delayed the spread of resistance but could, in specific circumstances that were thoroughly investigated, actually increase the rate of spread. Different spread dynamics were observed, with simulations leading to fixation, loss and most interestingly, equilibrium (without explicit overdominance) of the resistance allele. CONCLUSIONS: This strategy has the potential to delay the spread of resistance but note that in an heterogeneous environment it can also lead to the opposite effect, i.e., increasing the rate of spread. This clearly emphasizes that selection pressure acting inside the house cannot be treated in isolation but must be placed in context of overall insecticide use in an heterogeneous environment.

Exploratory trial to determine the efficacy of the PYthon and the PYthon Magnum slow-release insecticide ear tags for the control of midges (Culicoides spp.), attacking sheep and cattle and flies attacking cattle.

This study investigated the prophylactic action of the chemical combination zeta-cypermethrin and piperonyl butoxide, administered by means of slow-release insecticide-impregnated ear tags, against biting midges (Culicoides spp) attacking sheep and against midges, horn flies (Haematobia irritant), stable flies (Stomoxys calcitrans), and houseflies (Musca domestica) attacking cattle. Treated sheep and cattle were protected 100 percent against blood-feeding midges for two months and there was a clear reduction in the number of midges collected from treated animals. Three days after the ear tags were attached to cattle, the number of horn flies on the cattle was reduced to practically zero and remained at a low level until the end of the trial (day 85). There was also a strong reduction in the numbers of stable flies and houseflies counted.

Estimation of the percutaneous absorption of permethrin in humans using the parallelogram method.

The objective of this study was to develop an estimate of the percent dermal absorption of permethrin in humans to provide more accurate estimates of potential systemically absorbed dose associated with dermal exposure scenarios. Piperonyl butoxide (PBO) was used as a reference compound. The human percutaneous absorption estimate was based on the assumption that the ratio of in vivo dermal absorption (expressed as a percentage during a given time period) of permethrin through rat skin to in vitro dermal absorption through rat skin was the same as the ratio of in vivo dermal absorption in humans to in vitro dermal absorption with human skin, known as the parallelogram method. The ratio of dermal absorption by in vitro rat skin to absorption by in vitro human skin ranged from 6.7 to 15.4 (for a 24-h exposure period) with an average of 11. Data suggest in vivo human dermal absorption values for permethrin ranging from 1.4 to 3.3% when estimated based on 24-h in vivo rat values, and 2.5 to 5.7% based on 5-d in vivo rat values. The parallelogram method used to estimate dermal absorption of permethrin and PBO is supported by results from several other compounds for which in vivo and in vitro rat and human dermal absorption data exist. Collectively, these data indicate that estimating human dermal absorption from in vitro human and rat plus in vivo rat data are typically accurate within ±3-fold of the values measured in human subjects.

The effects of cypermethrin pour-on and piperonyl butoxide on Triatoma infestans under laboratory conditions.

The effect of exposing Triatoma infestans to chickens treated with cypermethrin pour-on combined with piperonyl butoxide (PBO) was studied. Four groups of treated chickens and one control group were used. Each treatment received 1 or 2 ml of the cypermethrin formulation with and without PBO. Independent groups of nymphs were fed 1, 7, 15, 30, and 45 d after the treatment application. Blood intake was estimated after each feeding occasion. Up to 15 d after the pour-on application, high mortality was observed in all nymphs fed on treated chickens (> 93% +/- 12), and lower than the nymphs of the control group (< 33% +/- 15). After 30 d of the pour-on application, there was significantly different mortality between the treatment with 1 ml (80% +/- 9) and 2 ml (> 96% +/- 5); no difference was observed between groups with or without PBO addition. After 45 d of the pour-on application, the treatments did not show significant differences (77% +/- 7), although all treatments showed higher mortality than the control group (10% +/- 9). Up to 45 d after the pour-on application, blood intake by nymphs exposed to treated chickens (0.85 +/- 0.96 mg/nymph) was lower than blood intake by nymphs exposed to control chickens (6.7 +/- 5 mg/nymph). This study shows that cypermethrin pour-on produces high mortality and reduces the blood intake of third-instar nymphs of T. infestans up to 45 d after the insecticide application to chickens. PBO did not produce a detectable effect.

A randomised, assessor blind, parallel group comparative efficacy trial of three products for the treatment of head lice in children--melaleuca oil and lavender oil, pyrethrins and piperonyl butoxide, and a "suffocation" product.

BACKGROUND: There are many different types of pediculicides available OTC in Australia. In this study we compare the efficacy and safety of three topical pediculicides: a pediculicide containing melaleuca oil (tea tree oil) and lavender oil (TTO/LO); a head lice "suffocation" product; and a product containing pyrethrins and piperonyl butoxide (P/PB). METHOD: This study was a randomised, assessor-blind, comparative, parallel study of 123 subjects with live head lice. The head lice products were applied according to the manufacturer's instructions (the TTO/LO product and the "suffocation" product were applied three times at weekly intervals according to manufacturers instructions (on Day 0, Day 7 and Day 14) and the P/PB product was applied twice according to manufacturers instructions (on Day 0 and Day 7)). The presence or absence of live lice one day following the last treatment was determined. RESULTS: The percentage of subjects who were louse-free one day after the last treatment with the product containing tea tree oil and lavender oil (41/42; 97.6%) and the head lice "suffocation" product (40/41, 97.6%) was significantly higher compared to the percentage of subjects who were louse-free one day after the last treatment with the product containing pyrethrins and piperonyl butoxide (10/40, 25.0%; adj. p < 0.0001). CONCLUSION: The high efficacy of the TTO/LO product and the head lice "suffocation" product offers an alternative to the pyrethrins-based product. TRIAL REGISTRATION: The study was entered into the Australian/New Zealand Clinical Trial Registry, ACTRN12610000179033.

Evaluation of efficacy and human health risk of aerial ultra-low volume applications of pyrethrins and piperonyl butoxide for adult mosquito management in response to West Nile virus activity in Sacramento County, California.

The Sacramento and Yolo Mosquito and Vector Control District (SYMVCD, also referred to as "the District") conducts surveillance and management of mosquitoes in Sacramento and Yolo counties in California. Following an increase in numbers and West Nile virus (WNV) infection rates of Culex tarsalis and Culex pipiens, the District decided on July 26, 2007, to conduct aerial applications of Evergreen EC 60-6 (60% pyrethrins: 6% piperonyl butoxide) over approximately 215 km2 in the north area of Sacramento County on the nights of July 30, July 31, and August 1, 2007. At the same time, the District received notification of the first human WNV case in the area. To evaluate the efficacy of the applications in decreasing mosquito abundance and infection rates, we conducted pre- and post-trapping inside and outside the spray zone and assessed human health risks from exposure to the insecticide applications. Results showed a significant decrease in abundance of both Cx. tarsalis and Cx. pipiens, and in the minimum infection rate of Cx. tarsalis. Human-health risks from exposure to the insecticide were below thresholds set by the US Environmental Protection Agency.

Repeated-dose 14-day dermal toxicity of different combinations of some synthetic pyrethroid insecticides, piperonyl butoxide, and tetramethrin in rats.

The aim of this study was to evaluate the repeated-dose 14-day dermal toxicity of different combinations of some synthetic pyrethroid insecticides, piperonyl butoxide, and tetramethrin in rats. A total of 70 adult Wistar rats were randomly divided into 7 (6 experimental and 1 control) groups. Different combinations of insecticides were dermally applied to the rats in the experimental groups for 14 days. Clinical observations were performed daily; hematologic and biochemical parameters were also determined. Gross necropsy and histopathologic examinations were performed systematically, and organ weights were recorded. Although the administered doses of the insecticides were relatively lower than their acute dermal toxicity values, a high mortality rate (27 of 60 experimental animals, 45%) was observed. Furthermore, the insecticide combinations caused decreased body weights and feed consumptions, increased organ weights, and hematologic, biochemical, and common histopathologic changes. As a result, the findings showed that although pyrethroids are considered to be of low acute toxicity, they become more toxic when combined with piperonyl butoxide or tetramethrin in certain doses.

Factors affecting Culicoides species composition and abundance in avian nests.

Mechanisms affecting patterns of vector distribution among host individuals may influence the population and evolutionary dynamics of vectors, hosts and the parasites transmitted. We studied the role of different factors affecting the species composition and abundance of Culicoides found in nests of the blue tit (Cyanistes caeruleus). We identified 1531 females and 2 males of 7 different Culicoides species in nests, with C. simulator being the most abundant species, followed by C. kibunensis, C. festivipennis, C. segnis, C. truncorum, C. pictipennis and C. circumscriptus. We conducted a medicationxfumigation experiment randomly assigning bird's nests to different treatments, thereby generating groups of medicated and control pairs breeding in fumigated and control nests. Medicated pairs were injected with the anti-malarial drug Primaquine diluted in saline solution while control pairs were injected with saline solution. The fumigation treatment was carried out using insecticide solution or water for fumigated and control nests respectively. Brood size was the main factor associated with the abundance of biting midges probably because more nestlings may produce higher quantities of vector attractants. In addition, birds medicated against haemoparasites breeding in non-fumigated nests supported a higher abundance of C. festivipennis than the rest of the groups. Also, we found that the fumigation treatment reduced the abundance of engorged Culicoides in both medicated and control nests, thus indicating a reduction of feeding success produced by the insecticide. These results represent the first evidence for the role of different factors in affecting the Culicoides infracommunity in wild avian nests.

Selection for imidacloprid resistance and mode of inheritance in the brown planthopper, Nilaparvata lugens.

BACKGROUND: Strong resistance to imidacloprid in Nilaparvata lugens (Stål) has developed in Southeast and East Asia. Although the mode of inheritance for resistance is very useful information for pest control, this information is unknown in N. lugens. Here, we established two resistant strains that were selected from field populations in Vietnam and the Philippines, and conducted crossing experiments to determine the inheritance pattern. RESULTS: The resistance ratio of 50% lethal dose (LD50 ) values for the two resistance-selected strains, i.e., resistant strains originating from Vietnam (VT-Res) and the Philippines (PH-Res), to their control strains were ∼ 8- and 157-fold, respectively. Reciprocal cross experiments between VT-Res and the susceptible strain (S-strain), and between PH-Res and the S-strain showed that the degree of dominance was 0.81 and 0.82, and 0.95 and 0.96, respectively. Analysis of the F2 populations and backcrosses to the parental strains indicated that resistance is a major-gene trait following Mendelian inheritance. The strength of the resistance was suppressed by pre-treatment with piperonyl butoxide, an inhibitor of cytochrome P450-monooxygenases. CONCLUSION: Our results suggest that imidacloprid resistance in N. lugens is autosomal and an almost completely dominant major-gene trait that is likely manifested by high expression levels of a detoxification enzyme. © 2019 Society of Chemical Industry.

Effect of synergist piperonyl butoxide (PBO) on the toxicity of some essential oils against mosquito larvae.

Effect of a known synergist piperonyl butoxide on the toxicity of steam distillate essential oils of Jamarosa (Cymbopogan nardus), Pacholli (Pogostemon pacholli), Basil (Ocimum basilicum), and Peppermint (Mentha pipreta) plant species against Anopheles stephensi larvae were evaluated. The purpose of the present study was to identify the insecticidal potential of these oils against mosquito larvae. The Piperonyl Butoxide (PBO) was used to enhance the activity of these oils with the aim of developing essential oil based formulations. The bioassays of these oils with and without PBO were performed against late 3rd instar larvae of An. stephensi. The LC50 values against An. stephensi were 44.19 ppm for Ocimum basilicum oil, followed by, Mentha pipreta, Cymbopogan nardus, and Pogostemon pacholli oil which gave LC50 values above 250 ppm. Thus in the present study the Ocimum basilicum oil was found to be most effective, whereas Pogostemon pacholli oil was found to least effective against mosquitoes for larvicidal action. The effect of synergist PBO led to the enhancement of toxicity of oils, the LC50 value for Ocimum basilicum were reduced from 44.19 ppm to 23.87 ppm. Similarly the oil of Pogostemon pacholli showed most significant results where the LC50 value was >250 ppm it was reduced to 50 ppm with PBO.

Temporal synergism by microencapsulation of piperonyl butoxide and alpha-cypermethrin overcomes insecticide resistance in crop pests.

A microencapsulated formulation that gives a burst release of piperonyl butoxide (PBO) several hours before a burst release of a conventional pyrethroid can effectively overcome metabolic resistance in Bemisia tabaci Gennadius, Helicoverpa armigera (Hübner), Aphis gossypii Glover and Myzus persicae Sulzer. This increase in efficacy against resistant pests was reflected in a field trial against B. tabaci on cotton, eliminating the need for two treatments. The ratio between the active insecticide and the synergist was found to be crucial in reducing resistance factors.

Ultra low volume aerosol application of deltacide (deltamethrin 0.5% w/v, S-bioallethrin 0.71% w/v & piperonyl butoxide 8.9% w/v) against mosquitoes.

BACKGROUND & OBJECTIVE: Insecticide in the form of space spray as an ultra low volume (ULV) aerosol are used during epidemics of vector borne diseases. Deltacide, a formulation comprising of three chemicals viz., deltamethrin 0.5 per cent w/v, S-bio-allethrin 0.71 per cent w/v and piperonyl butoxide 8.9 per cent w/v is suitable for ULV application. As this combination is found to be effective in preventing resistance development tackling the population, which had already developed resistance and cause immediate mortality, its synergistic effect was tested in Peet Grady chamber, against three species of mosquitoes, viz., Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus. METHODS: Blood fed females were exposed to ULV application of deltacide in a Peet Grady chamber at four dosages viz., 0.005, 0.01, 0.02 and 0.04 ml/m2 and examined for knockdown activity at 10 min interval for 60 min. Thereafter, the mosquitoes were removed from the chamber and maintained in another room having controlled temperature (28+/-2 degrees C) and humidity (60-75%) and observed for recovery, if any, and the per cent knockdown was calculated. Mortality rate after 24 h of holding period was also determined from moribund and dead adults. RESULTS: Pairwise comparison showed that the effect of deltacide spray varied significantly (P<0.001) among the three species tested. The effectiveness was significantly higher in Ae. aegypti, when compared with that of Cx. quiquefasciatus (P<0.001) and An. stephensi (P<0.05). However, there was no significant difference in the efficacy of deltacide between Cx. quiquefasciatus and An. stephensi. All species of mosquitoes became inactive i.e., knocked down completely within 60 min of exposure at all the dosages tested and mortality observed was 100 per cent after 24 h of exposure. INTERPRETATION & CONCLUSION: Deltacide when tested in the form of ULV cold aerosol, the dosage 0.01 ml/m2 was effective against both Ae. aegypti, and An. stephensi, and 0.02 ml/m2 against Cx. quiquefasciatus, causing 100 per cent mortality. The efficacy of ULV application of deltacide against vector mosquitoes needs to be assessed under field conditions.

Carcinogenesis bioassay of technical-grade piperonyl butoxide in F344 rats.

The insecticide synergist piperonyl butoxide--alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltoluene--was tested for carcinogenicity in inbred F344 rats in a 2-year study employing doses of 10,000 and 5,000 ppm of the compound administered continuously in the feed. Although a statistically significant dose-related increase in the incidence of lymphoreticular neoplasia was associated with administration of the compound to females, the incidence of that class of neoplasm was higher in control males than in treated males. The finding of statistical significance in one sex is not considered by itself to constitute sufficient evidence of a biologic effect to justify an indictment of carcinogenic action. However, inasmuch as the chief use of this substance is to alter the in vivo metabolism of other chemicals, its possible role as a cocarcinogen should be carefully considered in any risk-benefit evaluation aimed at setting policies regarding its uses.