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Richard C. Peffer

Bio: Richard C. Peffer is an academic researcher from Syngenta. The author has contributed to research in topics: Constitutive androstane receptor & Receptor. The author has an hindex of 10, co-authored 13 publications receiving 555 citations.

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TL;DR: The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans, supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.
Abstract: The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.

214 citations

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TL;DR: Findings at high doses were associated with evidence of systemic toxicity, which indicates that these neonicotinoid insecticides do not selectively affect the developing nervous system.
Abstract: A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood–brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system.

92 citations

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TL;DR: It is demonstrated that short-term liver effects of cyproconazole in mice are CAR-dependent and similar to those of phenobarbital, a known nongenotoxic rodent liver carcinogen.

79 citations

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TL;DR: The results demonstrate that the 5-amino acid insertion that typifies human CAR3 also imparts ligand-activated receptor function in other species' CAR while maintaining signature responses in each species to select CAR ligands.

61 citations

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TL;DR: Comparisons of the major metabolic pathways of thiamethoxam in vitro using mouse, rat, and human liver fractions have shown that metabolic rates in humans are lower than those in the rat suggesting that this chemical is unlikely to pose a hazard to humans exposed to this chemical at the low concentrations found in the environment or during its use as an insecticide.

52 citations


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TL;DR: In this paper, a review of the global literature explores these risks and show a growing body of evidence that persistent, low concentrations of these insecticides pose serious risks of undesirable environmental impacts.
Abstract: Since their discovery in the late 1980s, neonicotinoid pesticides have become the most widely used class of insecticides worldwide, with large-scale applications ranging from plant protection (crops, vegetables, fruits), veterinary products, and biocides to invertebrate pest control in fish farming. In this review, we address the phenyl-pyrazole fipronil together with neonicotinoids because of similarities in their toxicity, physicochemical profiles, and presence in the environment. Neonicotinoids and fipronil currently account for approximately one third of the world insecticide market; the annual world production of the archetype neonicotinoid, imidacloprid, was estimated to be ca. 20,000 tonnes active substance in 2010. There were several reasons for the initial success of neonicotinoids and fipronil: (1) there was no known pesticide resistance in target pests, mainly because of their recent development, (2) their physicochemical properties included many advantages over previous generations of insecticides (i.e., organophosphates, carbamates, pyrethroids, etc.), and (3) they shared an assumed reduced operator and consumer risk. Due to their systemic nature, they are taken up by the roots or leaves and translocated to all parts of the plant, which, in turn, makes them effectively toxic to herbivorous insects. The toxicity persists for a variable period of time—depending on the plant, its growth stage, and the amount of pesticide applied. A wide variety of applications are available, including the most common prophylactic non-Good Agricultural Practices (GAP) application by seed coating. As a result of their extensive use and physicochemical properties, these substances can be found in all environmental compartments including soil, water, and air. Neonicotinoids and fipronil operate by disrupting neural transmission in the central nervous system of invertebrates. Neonicotinoids mimic the action of neurotransmitters, while fipronil inhibits neuronal receptors. In doing so, they continuously stimulate neurons leading ultimately to death of target invertebrates. Like virtually all insecticides, they can also have lethal and sublethal impacts on non-target organisms, including insect predators and vertebrates. Furthermore, a range of synergistic effects with other stressors have been documented. Here, we review extensively their metabolic pathways, showing how they form both compound-specific and common metabolites which can themselves be toxic. These may result in prolonged toxicity. Considering their wide commercial expansion, mode of action, the systemic properties in plants, persistence and environmental fate, coupled with limited information about the toxicity profiles of these compounds and their metabolites, neonicotinoids and fipronil may entail significant risks to the environment. A global evaluation of the potential collateral effects of their use is therefore timely. The present paper and subsequent chapters in this review of the global literature explore these risks and show a growing body of evidence that persistent, low concentrations of these insecticides pose serious risks of undesirable environmental impacts.

1,131 citations

Journal ArticleDOI
TL;DR: In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis), which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis.

448 citations

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TL;DR: Relationships explain much of neonicotinoid comparative toxicology and provide the basis for continued and improved safety and effectiveness of this chemotype.
Abstract: Neonicotinoids are one of the three principal insecticide chemotypes. The seven major commercial neonicotinoids are readily biodegraded by metabolic attack at their N-heterocyclylmethyl moiety, heterocyclic or acyclic spacer, and N-nitroimine, nitromethylene, or N-cyanoimine tip. Phase I metabolism is largely dependent on microsomal CYP450 isozymes with situ selectivity in hydroxylation, desaturation, dealkylation, sulfoxidation, and nitro reduction. Cytosolic aldehyde oxidase is a nitroreductase for some neonicotinoids. Phase II metabolism involves methylation, acetylation, and formation of glucuronide, glucoside, amino acid, and sulfate- and glutathione-derived conjugates. Some neonicotinoids act as proinsecticides with metabolism to more potent nicotinic agonists. Pest resistance is more commonly due to synergist-reversible CYP450 detoxification than to nAChR mutants or variants. Metabolites in some cases contribute to mammalian hepatotoxicity and carcinogenesis and in others to enhanced plant vigor and stress shields. These relationships explain much of neonicotinoid comparative toxicology and provide the basis for continued and improved safety and effectiveness of this chemotype.

280 citations

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TL;DR: The aims here are to review studies on human neonicotinoid exposure levels, health effect, evaluation of potential toxicity and to suggest possible directions for future research.

243 citations

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TL;DR: This Guidance describes how to perform hazard identification for endocrine‐disrupting properties by following the scientific criteria which are outlined in Commission Delegated Regulation (EU) 2017/2100 and Commission Regulation 2018/605 for biocidal products and plant protection products, respectively.
Abstract: This Guidance describes how to perform hazard identification for endocrine-disrupting properties by following the scientific criteria which are outlined in Commission Delegated Regulation (EU) 2017/2100 and Commission Regulation (EU) 2018/605 for biocidal products and plant protection products, respectively.

239 citations