A survey of EPA/OPP and open literature data on selected pesticide chemicals tested for mutagenicity I. Introduction and first ten chemicals

Dearfield, Kerry L.; Stack, H.Frank; Quest, John A.; Whiting, Rick J.; Waters, Michael D.

doi:10.1016/0165-1110(93)90018-i

Cited by 49 publications

(23 citation statements)

References 74 publications

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“…An index with confidence limits overlapping zero indicates the mixture has additive toxicity. human lymphocytes and chromosomal as well as mitotic aberrations in peripheral blood lymphocytes (Axelred et al, 2002;Bajpayee et al, 2006;Dearfield et al, 1993;Eastman & Barry, 1992;Vijayaraghavan & Nagarajan, 1994). Since most chemicals are assumed to be additive in toxicity (DeLorenzo & Lorimar, 2003;Faust et al, 1993;Marking, 1977;Monosson, 2005;Steevens & Benson, 2001), the detection of synergistic interactions has significant implications for pesticide regulators and environmental managers.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of cytotoxicity and genotoxicity of pesticide mixtures on lymphocytes

Shaik

Jamil

et al. 2016

Toxicology Mechanisms and Methods

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The cytotoxicity and genotoxicity of pesticide mixtures viz. endosulfan + chlorpyrifos, chlorpyrifos + profenofos, and endosulfan + profenofos were evaluated on cultured human peripheral blood lymphocytes using assays for cell viability, and genotoxicity using chromosomal aberrations test and comet assay. The LC values for cytotoxicity were 3.50 μM, 4.18 μM, and 10.5 μM for profenofos, endosulfan, and chlorpyrifos respectively. When combined in equimolar concentrations, the LC values for cytotoxicity were 1.4 μM, 1.8 μM, and 2.0 μM for endosulfan + chlorpyrifos, chlorpyrifos + profenofos, and endosulfan + profenofos, respectively. Higher concentrations of individual pesticides (0.5-4.0 μM) but very low concentrations of pesticide mixtures caused significant DNA damage. Additive index values indicated a synergistic effect of toxicity for endosulfan + chlorpyrifos combination (1.12 TTU). The binary mixture of chlorpyrifos + profenofos showed an additive toxicity (0.46 TTU) while an antagonistic effect was observed for endosulfan + profenofos combination. Synergism could be due to these complementary pesticides simultaneously acting in different ways, magnifying their efficacy, whereas an additive interaction would imply that the chemicals are acting by the same mechanism and at the same target. Analysis of toxicity of pesticide mixtures may serve as important biomarker for occupational and household exposure to pesticides, with different modes of action.

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Section: Discussionmentioning

confidence: 99%

Evaluation of cytotoxicity and genotoxicity of pesticide mixtures on lymphocytes

Shaik

Jamil

et al. 2016

Toxicology Mechanisms and Methods

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“…In vitro and in vivo genetic toxicology data from the open literature were surveyed as previously described [Dearfield et al, 1993], and the genetic activity profile (GAP) for CP was developed jointly with the International Agency for Research on Cancer (IARC) to graphically display genetic toxicology data as a function of concentration or dose. Details for the schematic representation of the GAP for CP, depicted in Figure 3, can be found in Waters et al [1988] and in Lohman and Lohman [2000].…”

Section: Genetic Toxicology Datamentioning

confidence: 99%

An evaluation of the mode of action framework for mutagenic carcinogens case study: Cyclophosphamide

McCarroll

Keshava

Cimino

et al. 2008

Environ and Mol Mutagen

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In response to the 2005 revised US Environmental Protection Agency (EPA) Cancer Guidelines, a Risk Assessment Forum's Technical Panel has devised a strategy in which genetic toxicology data combined with other information are assessed to determine whether a carcinogen operates through a mutagenic mode of action (MOA). This information is necessary for EPA to decide whether age-dependent adjustment factors (ADAFs) should be applied to the cancer risk assessment. A decision tree has been developed as a part of this approach and outlines the critical steps for analyzing a compound for carcinogenicity through a mutagenic MOA (e.g., data analysis, determination of mutagenicity in animals and in humans). Agents, showing mutagenicity in animals and humans, proceed through the Agency's framework analysis for MOAs. Cyclophosphamide (CP), an antineoplastic agent, which is carcinogenic in animals and humans and mutagenic in vitro and in vivo, was selected as a case study to illustrate how the framework analysis would be applied to prove that a carcinogen operates through a mutagenic MOA. Consistent positive results have been seen for mutagenic activity in numerous in vitro assays, in animals (mice, rats, and hamsters) and in humans. Accordingly, CP was processed through the framework analysis and key steps leading to tumor formation were identified as follows: metabolism of the parent compound to alkylating metabolites, DNA damage followed by induction of multiple adverse genetic events, cell proliferation, and bladder tumors. Genetic changes in rats (sister chromatid exchanges at 0.62 mg/kg) can commence within 30 min and in cancer patients, chromosome aberrations at 35 mg/kg are seen by 1 hr, well within the timeframe and tumorigenic dose range for early events. Supporting evidence is also found for cell proliferation, indicating that mutagenicity, associated with cytotoxicity, leads to a proliferative response, which occurs early (48 hr) in the process of tumor induction. Overall, the weight of evidence evaluation supports CP acting through a mutagenic MOA. In addition, no data were found that an alternative MOA might be operative. Therefore, the cancer guidelines recommend a linear extrapolation for the risk assessment. Additionally, data exist showing that CP induces mutagenicity in fetal blood and in the peripheral blood of pediatric patients; thus, the ADAFs would be applied.

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“…The presence of chlorothalonil in the environment could be hazardous to humans and other nontarget organisms. Chlorothalonil has been shown to produce levels of DNA damage in the rats, mice, and hamsters (Dearfield et al, 1993), and chromosomal alterations in the same animal species (Lebailly et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Embryotoxicity of oral administered chlorothalonil in mice

Farag

Karkour

Okazy

2006

Birth Defects Research Pt B

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A survey of EPA/OPP and open literature data on selected pesticide chemicals tested for mutagenicity I. Introduction and first ten chemicals

Cited by 49 publications

References 74 publications

Evaluation of cytotoxicity and genotoxicity of pesticide mixtures on lymphocytes

Evaluation of cytotoxicity and genotoxicity of pesticide mixtures on lymphocytes

An evaluation of the mode of action framework for mutagenic carcinogens case study: Cyclophosphamide

Embryotoxicity of oral administered chlorothalonil in mice

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