Building Confidence in New Evidence Streams for Human Health Risk Assessment Lessons Learned from Laboratory Mammalian Toxicity Tests (2023) / Chapter Skim
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3 Variability
3 Variability
Pages 35-60
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EXPERIMENTAL VARIABILITY IN LABORATORY MAMMALIAN TOXICITY STUDIES As mentioned in the previous chapters and discussed extensively in the 2007 report Toxicity Testing in the 21st Century: A Vision and a Strategy, animal toxicity studies have a long history of use. Early animal toxicity studies were performed using a variety of different animal species, housing conditions, and study designs and methods (Jacobs and Hatfield, 2013)
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BIOLOGICAL VARIABILITY IN LABORATORY MAMMALIAN TOXICITY STUDIES As defined in Chapter 2, biological variability is the true differences in attributes due to heterogeneity or diversity. Complex biological systems are intrinsically variable in their response to both endogenous and exogenous stressors, such as chemicals, due to the stochastic nature of biological systems on a chemical, molecular, cellular, tissue, organ, and organismal level.
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Multiple sources of potential biological variability have been identified in laboratory mammalian toxicity studies, including the genetic and epigenetic differences between species and between individuals within a species, sex, and developmental stage of the test organism or system, previous or concurrent exposures, or health status. For multiple reasons, biological variability (e.g., biological diversity)
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Acknowledging some of the shortcomings of the existing toxicity tests can help identify potential areas of opportunity where NAMs can fill data gaps. For example, laboratory mammalian toxicity studies usually use a small number of young, healthy animals.
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Relevant to variability in laboratory mammalian toxicity studies were the case studies on mixtures and DNT, as discussed subsequently. Mixtures This case study suggested that mixture studies provide an opportunity to assess the variability in laboratory mammalian toxicity studies because variability was represented in analyses where multiple chemicals were evaluated to establish toxicity equivalency factors (TEFs)
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The following goal was used to guide the literature review on variability: To summarize the systematic reviews and authoritative reviews (see Appendix C for definition) that assess and evaluate variability of laboratory mammalian toxicity studies.
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Systematic reviews judged to be of critically low quality were not considered further by the committee. Data on variability of laboratory mammalian toxicity studies were sought from the remaining 24 studies, as summarized in Table 3-1.
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Andrade et Rats and mice Resveratrol Alveolar bone loss and Conducted a systematic review and meta-analysis of seven mammalian al.
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other outcomes studied and mortality, respectively, following focal cerebral ischemia; 73% and in systematic reviews were beneficial in 58% for the effects of tirilazad on infarct volume and neurobehavior, of clinical trials nature respectively, following focal cerebral ischemia; and 73% for the effects of corticosteroids on mortality in the neonatal respiratory distress syndrome (discussed further in the text)
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Some of this heterogeneity could be explained by aspects of study design including dose, duration of exposure, and the tissue in which antioxidant effects were sampled.
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across multiple laboratory mammalian toxicity studies. electromagnetic fields in the The authors noted that there was large heterogeneity in study intermediate frequency range designs, investigated systems, and endpoints.
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rats, guinea pigs, treat chronic lung disease any harm, and, for the quantitative) across multiple laboratory mammalian toxicity studies.
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medicinal mushroom) across multiple laboratory mammalian toxicity studies.
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Overall, these systematic reviews and meta-analyses report moderate to high variability in the data analyzed. The authors were able to attribute part of the variability to study design elements that were not consistent across the studies analyzed such as the exact type of drug or chemical, sex, 48
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The findings from these studies are summarized in Table 3-3, but any conclusions about the qualitative and quantitative variability of laboratory mammalian toxicity studies derived from these reviews are to be interpreted with caution. Overall, these peer-reviewed papers report low to moderate qualitative variability based on the data they analyzed and generally less than a log difference in quantitative variability.
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Rats Chemicals with multiple rat chronic Chronic oral rat In the Nestle database, there were 93 compounds with multiple studies (2018) rat toxicity studies as collated in two LOAEL and reported mean standard deviation (SD)
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(2016) pigs laboratory mammalian sensitivity 95% for Buehler (344 chemicals)
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Reported Results Mazzatorta et Rats 94 chemicals with repeat dose Repeat dose systemic toxicity The interlab reproducibility of LOAEL values can be al.
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; in rats Kappa values ranged 0.21 (fair agreement) to 0.75 (substantial agreement)
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• There are examples where variability data from laboratory mammalian toxicity tests can serve as a benchmark for NAMs especially when the NAM or battery of NAMs are intended as a one-to-one replacement (e.g., skin sensitization)
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Findings related to the literature review and literature presented to the committee: • The literature search revealed that there is a lack of systematic reviews designed to eval uate variability in laboratory mammalian studies. Thus, the committee derived insights on variability from heterogeneity reported in meta-analyses based on systematic reviews and authoritative reviews not specifically intended for that purpose.
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Recommendation 3.6: If the EPA were to continue to pursue variability information from laboratory mammalian toxicity tests for benchmarking NAMs or batteries of NAMs intended as a direct replacement for an in vivo mammalian toxicity test, it should only use data from high-quality systematic reviews, meta-analyses, or authoritative reviews, or from interlaboratory studies using predetermined protocols and methods. REFERENCES Andersen, J
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2021. "Antileukotrienes for the Prevention and Treatment of Chronic Lung Disease in Very Preterm Newborns: A Systematic Review." Respiratory Research 22(1)
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2019. "Systematic Review and Meta-Analysis of the Behavioral Effects of Methylphenidate in the Spontaneously Hypertensive Rat Model of Attention-Deficit/hyperactivity Disorder." Neuroscience and Biobehavioral Reviews 100 (May)
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2020. "Perinatal Selective Serotonin Reuptake Inhibitor Exposure and Behavioral Out comes: A Systematic Review and Meta-Analyses of Animal Studies." Neuroscience and Biobehavioral Reviews 114 (July)
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2021. "Devel opment of a Range of Plausible Noncancer Toxicity Values for 2,3,7,8-Tetrachlorodibenzo P-Dioxin Based on Effects on Sperm Count: Application of Systematic Review Methods and Quantitative Integration of Dose Response Using Meta-Regression." Toxicological Sciences: An Official Journal of the Society of Toxicology 179(2)
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