Pyrethroid neurotoxicity studies with bifenthrin indicate a mixed Type I/II mode of action.

BACKGROUND: Bifenthrin is usually considered a Type I pyrethroid, because it lacks an α-CN group present in Type II pyrethroids, but some previous studies suggest a mixed Type I/II mode-of-action. Results are presented for bifenthrin in a rat developmental neurotoxicity (DNT) study along with effects on Na currents in human VGSC subtypes. Molecular modeling comparisons were also made for bifenthrin and other pyrethroids. RESULTS: In a rat DNT study, bifenthrin produced tremors and clonic convulsions in dams and pups and slightly reduced acoustic startle response amplitude, and increased Tmax, at PND20 in females. Similar blood levels of bifenthrin were measured in dams and pups at each dose level i.e. no concentration in pups. In human VGSC experiments, using the Nav1.8 subtype, bifenthrin's effects on inactivation were slight, as for Type II pyrethroids, but without large prolongation of the tail current (deactivation) seen with Type II. Molecular modeling of bifenthrin indicates that the o-Me group may occupy a similar space to the α-CN group of cypermethrin and fenpropathrin. CONCLUSION: In a DNT study and on human Nav1.8 tail currents bifenthrin showed Type I and II effects, similar to some published studies. Overall, bifenthrin acts as a mixed Type I/II pyrethroid. © 2018 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Carbofuran occupational dermal toxicity, exposure and risk assessment.

BACKGROUND: Carbofuran is a carbamate insecticide that inhibits AChE. Although toxic by ingestion in mammals, it has low dermal toxicity, with relatively few confirmed worker illnesses. This risk assessment describes its time of onset, time to peak effect and time to recovery in rats using brain AChE inhibition in acute and 21 day dermal studies; in vitro rat/human relative dermal absorption for granular (5G) and liquid (4F) formulations; occupational exposure estimates using the Pesticide Handlers' Exposure Database and Agricultural Handlers' Exposure Database (PHED/AHED). RESULTS: The point of departure for acute risk calculation (BMDL(10)) was 6.7 mg kg(-1) day(-1) for brain AChE inhibition after 6 h exposure. In a 21 day study, the BMDL(10) was 6.8 mg kg(-1) day(-1), indicating reversibility. At 75 mg kg(-1) day(-1), time of onset was ≤ 30 min and time to peak effect was 6-12 h. Rat skin had ca tenfold greater dermal absorption of carbofuran (Furadan(®) 5G or 4F) than human skin. Exposure estimates for 5G in rice and 4F in ten crops had adequate margins of exposure (>100). CONCLUSION: Rat dermal carbofuran toxicity was assessed in terms of dose and time-related inhibition of AChE. Comparative dermal absorption in rats was greater than in humans. Worker exposure estimates indicated acceptable risk for granular and liquid formulations of carbofuran.

Pyrethroid mode(s) of action in the context of Food Quality Protection Act (FQPA) regulation.

A Scientific Advisory Panel (SAP) in June 2009 concluded that a common mode of action existed for pyrethroids, with two subgroups. The purpose of this SAP was to advise the U.S. Environmental Protection Agency on the validity of regulation of pyrethroids as a single class under the Food Quality Protection Act of 1996. Two types of pyrethroid action were first described for clinical signs in the rat and clinical signs/nerve effects in the cockroach. In insects, Type I clinical signs correlate with repetitive firing in nerve axons, especially fine sensory axons. The Na(+) inward current is via a TTX-sensitive voltage-gated sodium channel (VGSC). Type II (α-CN) effects on VGSCs do not include repetitive firing following stimulation in these axons. Instead, Type II effects on VGSCs include prolonged Na(+) tail currents along with depolarization of nerve membrane. Other Type II effects have been measured on VG Ca(2+) and K(+) channels and VG and GABA-activated Cl(-) channels. In conclusion, in vivo pyrethroid effects in mammals should be linked with specific channel effects, allowing the use of specific clinical signs or ion channel effects for pyrethroid risk assessment.

Public safety aspects of pyrethroid insecticides used in West Nile virus-carrying mosquito control.

West Nile virus is becoming increasingly prevalent in the USA, causing fever, encephalitis, meningitis and many fatalities. Spread of the disease is reduced by controlling the mosquito vectors by a variety of means, including the use of pyrethroid insecticides, which are currently under scrutiny for potential carcinogenic effects in humans. Pyrethrins and resmethrin, a pyrethroid, have been shown to cause tumours in rat and mouse models respectively. However, the tumours appear to be caused by liver enzyme induction and hypertrophy rather than genotoxicity, and the results are therefore unlikely to be applicable to humans. Nonetheless, for resmethrin, the US Environmental Protection Agency (EPA) has concluded that there is a likely risk of carcinogenicity in humans, requiring the manufacturers to provide more detailed data to prove that it can be used safely in vector control. Reproductive toxicity of resmethrin in the rat is also discussed.

A dietary risk assessment of the pyrethroid insecticide resmethrin associated with its use for West Nile Virus mosquito vector control in California.

An outbreak of human illnesses associated with West Nile Virus (WNV) occurred in New York City in 1999. Since then, it has gradually spread westwards, reaching northern California for the first time in 2005. WNV is transmitted by several mosquito species and birds serve as the main reservoir. Several control measures have been used, targeting both the aquatic larvae and the adult mosquitoes. In the latter case, roosting birds in trees are sprayed with pyrethroid insecticides because these are highly toxic to mosquitoes, but have low avian toxicity. A request was made to use a resmethrin-containing insecticide during the month of October 2005 in California. Because resmethrin was not registered for use on growing crops, concerns were raised about potential crop contamination. Therefore, an expedited dietary risk assessment was conducted on resmethrin. Developmental toxicity in the rat (NOELs of 25 or 40 mg/kg/day) was used as the acute endpoint and dietary exposure was assessed using the DEEM-FCID computer program. Only crops growing above ground during October were considered. Margins of Safety (MOS) were found to be above 100, the level generally considered to be sufficient to protect public health when using an animal NOEL.

A risk assessment of atrazine use in California: human health and ecological aspects.

A risk assessment of the triazine herbicide atrazine has been conducted by first analyzing the toxicity database and subsequently estimating exposure. Margins of safety (MOS) were then calculated. Toxicity was assessed in animal studies and exposure was estimated from occupational and dietary sources. In acute toxicity studies, atrazine caused developmental toxicity in the rabbit [no observed effect level (NOEL) 5 mg kg(-1) day(-1)] and cardiotoxicity in a dog chronic study (NOEL 0.5 mg kg(-1) day(-1)); cancer (mammary glands) resulted from lifetime exposure. The mammary tumors, which occurred specifically in female Sprague-Dawley rats, were malignant, increased in a dose-dependent manner and were also observed with other, related triazines. Evidence for a genotoxic basis for these tumors was either equivocal or negative. Triazines have been shown to be clastogenic in Chinese hamster ovary cells, in vitro, but without showing a convincing dose/response relationship. Atrazine can be converted into genotoxic N-nitrosoatrazine in the environment or the digestive system, suggesting that N-nitrosamines derived from triazines could be oncogenic. However, it was concluded that N-nitrosotriazines are unlikely to play a significant role in triazine-induced rat mammary gland tumors. An endocrine basis for the mammary tumors, involving premature aging of the female SD rat reproductive system, has been proposed. A suppression of the luteinizing hormone surge during the estrus cycle by atrazine leads to the maintenance of elevated blood levels of 17beta-estradiol (E2) and prolactin. The mechanism for tumor development may include one or more of the following: the induction of aromatase (CYP19) and/or other P450 oxygenases, an antagonist action at the estrogen feedback receptor in the hypothalamus, an agonist action at the mammary gland estrogen receptor or an effect on adrenergic neurons in the hypothalamic-pituitary pathway. None of these has been excluded as a target because there has been a lack of a rigorous attempt to address the mechanism of action for mammary tumors at the molecular level. The potential occupational exposure to atrazine was assessed during mixing, loading and application. Absorbed daily dosage values were 1.8-6.1 microg kg(-1) day(-1). The MOS values (animal NOEL/human exposure) for short-term (acute) exposure were 820-2800. Longer-term occupational exposure and risk were also calculated. Detectable crop residues are generally absent at harvest. Theoretical calculations of acute dietary exposure used tolerance levels, along with secondary residues, and water, for which there is a maximum contamination level; atrazine plus the three main chlorotriazine metabolites were combined. MOS values were above 2000 for all population subgroups. Dietary exposure to atrazine is therefore extremely unlikely to result in human health hazard. Recent publications have reported a possible feminization of frogs, measured in laboratory and field studies. This is assumed to be due to the induction of aromatase, but no measurements of enzyme activity have been reported. In field studies, the water bodies with the greatest numbers of deformed frogs sometimes had the lowest concentrations of atrazine. Other studies have also cast doubt on the feminization theory, except perhaps at very high levels of atrazine. Epidemiology studies have investigated the possibility that atrazine may result in adverse effects in humans. Although some studies have claimed that atrazine exposure results in an elevated risk of prostate cancer, the published literature is inconclusive with respect to cancer incidence.