Assessment of diurnal systemic dose of agrochemicals in regulatory toxicity testing – An integrated approach without additional animal use

Saghir, Shakil A.; Bartels, Michael; Rick, David L.; McCoy, Alene T.; Rasoulpour, Reza J.; Ellis-Hutchings, Robert G.; Marty, M. Sue; Terry, Claire; Bailey, Jason P.; Billington, Richard; Bus, James S.

doi:10.1016/j.yrtph.2012.03.004

Cited by 51 publications

(18 citation statements)

References 22 publications

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“…These doses were anticipated to be either at or slightly above the inflection point for non-linear TK behavior of 2,4-D, considered a threshold for saturation of renal clearance (TSRC) for each respective gender (also referred to as a KMD or kinetically derived maximum dose in some reports, Saghir et al 2012). Data from the EOGRT TK range finder study showed that the high dose for male rats (800 ppm; 41 mg/kg/day) was close to, but slightly above the TSRC.…”

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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“…A pragmatic solution could be to consider collecting toxicokinetic data as part of standard toxicological studies. Saghir et al (2012) and Creton (2012) outlined overviews of how toxicokinetic parameters could be included in standard guideline studies from sub-acute to chronic repeated-dose toxicity studies and developmental and reproductive toxicity studies. The approach proposed considering measurements taken during the range finding of a study, therefore using a limited number of animals and avoiding the use of radiolabelled material.…”

Section: Principle and Considerationsmentioning

confidence: 99%

“…ADME information could be conceivably generated as part of a range finding study. Saghir et al, (2012) and Creton et al, (2012) recently published overviews of the possible inclusion of toxicokinetic parameters in standard guideline studies from sub-acute to chronic repeated-dose toxicity studies, developmental and reproductive toxicity studies. The addition of toxicokinetic parameters to standard toxicological studies could be performed relatively inexpensively, does not require the use of radiolabelled material by default and measurements can be taken during the range finding study using a limited number of animals, thus not increasing the total number of animals used overall (ECETOC, 2012;Patlewicz et al, 2013).…”

Section: Metabolic or Degradation Pathways And Toxicokineticsmentioning

confidence: 99%

Guidance on Grouping of Chemicals, Second Edition

2017

OECD Series on Testing and Assessment

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“…Using this approach across study types in a testing program will provide important information for understanding the relationship between the systemic dose and toxicity. Additionally, due to innovative sampling techniques, this data can be achieved without the need for satellite animals [18,19], thus reducing animal demands.…”

Section: Typical Flow and Integration Of Studies For Industrial Chemimentioning

confidence: 99%

“…Comparison studies of exposure routes in the rabbit demonstrated that with a short half-life molecule (t 1/2 ¼ 1 h), there was a striking difference in diurnal fluctuation between C max and C min , with only sixfold difference by dietary exposure, compared to a 368-fold difference by gavage [17,18]. Additionally, this molecule was detectable only up to 12 h by gavage but up to 24 h by dietary administration.…”

Section: Typical Flow and Integration Of Studies For Industrial Chemimentioning

confidence: 99%

A Developmental and Reproductive Toxicology Program for Chemical Registration

Johnson

Hannas

Marty

et al. 2016

Methods in Pharmacology and Toxicology

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The goal of the chapter is to outline the process of testing molecules for potential developmental and reproductive toxicity (DART). Here, the entire process of DART testing is discussed, from the regulatory use of DART data to the conduct and interpretation of the various DART study designs. Although nonanimal DART testing strategies are envisioned by the new science of "21st Century Toxicity Testing", these high-content, high-throughput testing paradigms are not sufficiently mature from a scientific perspective to be acceptable on their own by regulatory agencies for chemical registration. Thus, these testing paradigms are not included in this chapter. While the scope of the chapter is broad, it is beyond the range of this chapter to describe all possible scenarios encountered in DART testing. For additional information, the reader is referred to other recent publications on this topic. The chapter is organized in a stepwise manner into three main topics: (1) Use of DART studies for chemical registration; (2) General considerations for all DART study designs; and (3) Descriptions of all DART study designs from a practical perspective, beginning with an initial range-finding study and ending with the complex Extended One-Generation Reproductive Toxicity Study (EOGRTS).

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Assessment of diurnal systemic dose of agrochemicals in regulatory toxicity testing – An integrated approach without additional animal use

Cited by 51 publications

References 22 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

Guidance on Grouping of Chemicals, Second Edition

A Developmental and Reproductive Toxicology Program for Chemical Registration

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