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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4 Concordance with Human Data
4 Concordance with Human Data
Pages 61-80
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From page 61... ...
when they cannot be compared directly with human studies. Specifically, this chapter addresses the following charge question to the committee: What do the literature review and workshops indicate about concordance between labora tory mammalian models and humans in the adverse effects following chemical exposure and how might this frame expectations of NAMs when they cannot be compared directly with human studies?
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Presentations and round table discussions involving the presenters addressed topics including how laboratory mammalian toxicity studies are used to inform chemical safety decisions, some examples of variability and concordance of laboratory mammalian toxicity studies, and a consideration of the expectations of different stakeholders. A summary of the workshop proceedings was published (NASEM, 2022a)
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. • In addition, some workshop participants noted that many current laboratory mammalian toxicity tests are decades old and were designed to detect catastrophic effects (i.e., overt effects such as lethality, cancer, malformations, or histopathological changes in target organs)
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The presenters noted that it is difficult to evaluate concordance with humans of guideline DNT laboratory mammalian studies because very few tests have been done, they are often not repeated, and the traditional DNT tests do not fully capture the dynamic nature of development and the timescale to detect adversity following developmental exposures. This is further elaborated in the following PBDE systematic review.
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statements, the inclusion and exclusion criteria, the literature search strategy, the process to assess methodological quality, and the analysis plan. This chapter focuses on the following goal: To summarize the systematic reviews and authoritative reviews that assess the concordance of adverse health effects between laboratory mammalian models and humans following ex posures to environmental agents.
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, hypospadias, and fetal testosterone. To summarize the included animal studies that met the review criteria: • 19 animal studies assessed the association between DEHP exposure and AGD with "a high confidence rating of the body of evidence … and … a high level of evidence that fetal exposure to DEHP is associated with a reduction in AGD in male rats" (NASEM, 2017, p.
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in systematic reviews of clinical trials Bestry et al.
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(2021) Humans, mice, rats, Antileukotrienes to All-cause mortality and any Limited ability to evaluate concordance due to heterogeneity in study guinea pigs, prevent or treat harm, and, for the clinical designs, methods, and high level of bias.
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(2021) Humans and rats Exposure to dioxin Reduced sperm count Limited ability to evaluate concordance due to methodological 69 like compounds deficiencies, including deviation from protocol.
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Across studies in rats and mice, the committee noted a significant relationship between PBDE exposure and changes in the latency to complete the last trial of a Morris water maze. Challenges to this interpretation include analysis across all congeners, which likely have different potencies for these effects, variability in timing of exposure and testing, and not accounting for sex differences, which are substantial in this testing paradigm.
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Lessons learned from this element of the 2017 NASEM report analyzing the association between PBDE exposure and neurodevelopment are similar to those identified for phthalate exposure and male reproductive development. • High risk-of-bias ratings for multiple questions in the individual animal studies resulted in the subsequent downgrading of the overall level of confidence in the bodies of evi dence.
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This systematic review abstracted animal studies for interventions with clear evidence of either a beneficial or harmful treatment effect in clinical trials, and one included bisphosphonates to treat osteoporosis. Bisphosphonates increase bone mineral density of the lumbar spine and hip as measured by dual energy absorptiometry (DXA)
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However, many leveraged data sets culled from the literature that could in part be identified via a systematic review, though additional studies could also be identified. All the papers cited in the workshops not previously identified as part of the committee's literature review were regarded as having critically low methodological quality because they were not systematic reviews.
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(2021) Humans, rats, mice Per‐ and polyfluoroalkyl Health effects Concordance was generally seen between animal studies and substances (PFAS)
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NRC (2000) Humans, rats, mice, Chemical and physical Developmental defects The report noted concordance of developmental effects rabbits agents between experimental animals and humans, and humans are as sensitive or more sensitive than the most sensitive animal species.
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• The committee's overview review established that there are few high-quality systematic reviews with evidence to evaluate concordance. • Literature cited during the information gathering sessions and workshop represent those selected as being of importance by speakers rather than through a more systematic pro cess that would minimize bias.
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Recommendation 4.3: In order to implement the recommendations from the report, the EPA, in collaboration with other agencies and the OECD, should convene scientific advisory groups that include appropriate subject matter and community health expertise, including clinicians, to review and update mammalian toxicity testing study designs to make them more specific, more sensitive, and better aligned with the 3 R goals. This process should provide opportunities to add endpoints with human relevance that are inadequately covered in laboratory mammalian toxicity tests such as DNT and mammary gland effects.
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2019. Concordance between sites of tumor development in humans and in experimental animals for 111 agents that are carcinogenic to humans.
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2014. "Animal versus Human Oral Drug Bioavailability: Do They Correlate?
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2017. "AMSTAR 2: A Critical Appraisal Tool for Systematic Reviews That Include Randomised or Non-Randomised Studies of Healthcare Interventions, or Both." BMJ 358 (September)
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