A Tiered Approach to Life Stages Testing for Agricultural Chemical Safety Assessment

Cooper, Ralph L.; Lamb, James C.; Barlow, Sue; Bentley, Karin S.; Brady, A.M.; Doerrer, Nancy G.; Eisenbrandt, David L.; Fenner-Crisp, Penelope A.; Hines, Ronald N.; Irvine, Lorraine; Kimmel, Carole A.; Koëter, H.B.W.M.; Li, Abby A.; Makris, Susan L.; Sheets, Larry P.; Speijers, G.J.A.; Whitby, Karen E.

doi:10.1080/10408440500541367

Cited by 148 publications

(80 citation statements)

References 26 publications

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“…Non-linear TK, in which metabolism or excretion pathways available at lower blood concentrations are partly or fully saturated with increasing dose, may be a clear confounder both in appropriately designing toxicological studies and evaluating results for hazard and human risk assessment. Use of TK to inform human-relevant dose selection in animal toxicity studies has been affirmed in recent reviews and Organization for Economic Cooperation and Development (OECD) guidance on conduct of the EOGRT study Carmichael et al 2006;Cooper et al 2006;OECD 443, 2012a). The guidance recommended that top dose level(s) should not exceed the inflection point of onset of TK non-linearity if the inflection point dose was well separated from human exposures, and further concluded that toxicity limited to doses above the onset of non-linear TK behavior was not quantitatively relevant to human risk.…”

Section: Differentiating Potential Endocrine Modes Of Action Based Onmentioning

confidence: 99%

Weight-of-the-evidence evaluation of 2,4-D potential for interactions with the estrogen, androgen and thyroid pathways and steroidogenesis

Neal

Marty

Coady

et al. 2017

Critical Reviews in Toxicology

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A comprehensive weight-of-the-evidence evaluation of 2,4-dichlorophenoxyacetic acid (2,4-D) was conducted for potential interactions with the estrogen, androgen and thyroid pathways and with steroidogenesis. This assessment was based on an extensive database of high quality in vitro, in vivo ecotoxicological and in vivo mammalian toxicological studies. Epidemiological studies were also considered. Toxicokinetic data provided the basis for determining rational cutoffs above which exposures were considered irrelevant to humans based on exceeding thresholds for saturation of renal clearance (TSRC); extensive human exposure and biomonitoring data support that these boundaries far exceed human exposures and provide ample margins of exposure. 2,4-D showed no evidence of interacting with the estrogen or androgen pathways. 2,4-D interacts with the thyroid axis in rats through displacement of thyroxine from plasma binding sites only at high doses exceeding the TSRC in mammals. 2,4-D effects on steroidogenesis parameters are likely related to high-dose specific systemic toxicity at doses exceeding the TSRC and are not likely to be endocrine mediated. No studies, including high quality studies in the published literature, predict significant endocrine-related toxicity or functional decrements in any species at environmentally relevant concentrations, or, in mammals, at doses below the TSRC that are relevant for human hazard and risk assessment. Overall, there is no basis for concern regarding potential interactions of 2,4-D with endocrine pathways or axes (estrogen, androgen, steroidogenesis or thyroid), and thus 2,4-D is unlikely to pose a threat from endocrine disruption to wildlife or humans under conditions of real-world exposures.ARTICLE HISTORY

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Section: Differentiating Potential Endocrine Modes Of Action Based Onmentioning

confidence: 99%

Weight-of-the-evidence evaluation of 2,4-D potential for interactions with the estrogen, androgen and thyroid pathways and steroidogenesis

Neal

Marty

Coady

et al. 2017

Critical Reviews in Toxicology

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“…At present, the two-Generation Reproductive Toxicity study based on OECD TG 416 of 2001 is required in the respective Regulations. However, animal numbers for reproductive toxicity testing could be reduced by up to 50% compared to the two-Generation study by using the EORGTS (Cooper et al, 2006). Moreover, the EGORTS is designed to include additional endpoints (neurotoxicity, immunotoxicity, endocrine-mediated toxicity), which may further decrease the number of animals used for risk assessment.…”

Section: Data Evaluationmentioning

confidence: 99%

Inconsistencies in data requirements of EU legislation involving tests on animals

Wagner¹

2012

ALTEX

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“…rabbit), if the reproduction study is conducted on another species (such as rat or mouse) (Hurtt et al, 2003;Cooper et al, 2006).…”

Section: Reproductive and Developmental Toxicity Testingmentioning

confidence: 99%

Safety and Nutritional Assessment of GM Plants and derived food and feed: The role of animal feeding trials

2008

EFS2

119

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In this report the various elements of the safety and nutritional assessment procedure for genetically modified (GM) plant derived food and feed are discussed, in particular the potential and limitations of animal feeding trials for the safety and nutritional testing of whole GM food and feed. The general principles for the risk assessment of GM plants and derived food and feed are followed, as described in the EFSA guidance document of the EFSA Scientific Panel on Genetically Modified Organisms.In Section 1 the mandate, scope and general principles for risk assessment of GM plant derived food and feed are discussed. Products under consideration are food and feed derived from GM plants, such as maize, soybeans, oilseed rape and cotton, modified through the introduction of one or more genes coding for agronomic input traits like herbicide tolerance and/or insect resistance. Furthermore GM plant derived food and feed, which have been obtained through extensive genetic modifications targeted at specific alterations of metabolic pathways leading to improved nutritional and/or health characteristics, such as rice containing b-carotene, soybeans with enhanced oleic acid content, or tomato with increased concentration of flavonoids, are considered.The safety assessment of GM plants and derived food and feed follows a comparative approach, i.e. the food and feed are compared with their non-GM counterparts in order to identify intended and unintended (unexpected) differences which subsequently are assessed with respect to their potential impact on the environment, safety for humans and animals, and nutritional quality. Key elements of the assessment procedure are the molecular, compositional, phenotypic and agronomic analysis in order to identify similarities and differences between the GM plant and its near isogenic counterpart.The safety assessment is focussed on (i) the presence and characteristics of newly expressed proteins and other new constituents and possible changes in the level of natural constituents beyond normal variation, and on the characteristics of the GM food and feed, and (ii) the possible occurrence of unintended (unexpected) effects in GM plants due to genetic modification. In order to identify these effects a comparative phenotypic and molecular analysis of the GM plant and its near isogenic counterpart is carried out, in parallel with a targeted analysis of single specific compounds, which represent important metabolic pathways in the plant like macro and micro nutrients, known anti-nutrients and toxins. Significant differences may be indicative of the occurrence of unintended effects, which require further investigation.Section 2 provides an overview of studies performed for the safety and nutritional assessment of whole food and feed. Extensive experience has been built up in recent decades from the safety and nutritional testing in animals of irradiated foods, novel foods and fruit and vegetables. These approaches are also relevant for the safety and nutritional testing of whole GM food...

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A Tiered Approach to Life Stages Testing for Agricultural Chemical Safety Assessment

Cited by 148 publications

References 26 publications

Weight-of-the-evidence evaluation of 2,4-D potential for interactions with the estrogen, androgen and thyroid pathways and steroidogenesis

Weight-of-the-evidence evaluation of 2,4-D potential for interactions with the estrogen, androgen and thyroid pathways and steroidogenesis

Inconsistencies in data requirements of EU legislation involving tests on animals

Safety and Nutritional Assessment of GM Plants and derived food and feed: The role of animal feeding trials

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