The Weight of Evidence Does Not Support the Listing of Styrene as “Reasonably Anticipated to be a Human Carcinogen” in NTP's Twelfth <i>Report on Carcinogens</i>

Rhomberg, Lorenz R.; Goodman, Julie E.; Prueitt, Robyn L.

doi:10.1080/10807039.2012.650577

Cited by 10 publications

(5 citation statements)

References 43 publications

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“…Similarly, it is not surprising that there is a lack of consistency in the tumorigenic potential noted in the NTP studies as compared to analogous tests conducted by others. 32,33 It is also not surprising that there is a serious challenge presented by a false-positive rate yet to be accurately quantitated.…”

Section: Introductionmentioning

confidence: 99%

The “false-positive” conundrum in the NTP 2-year rodent cancer study database

Smith

Perfetti²

2018

Toxicology Research and Application

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In 1990, Ames and Gold described a conundrum of "too many carcinogens" among chemicals tested in rodent bioassays. Their proposed nongenotoxic carcinogenic mechanism was amplification of the background mutation rate via cytotoxicity induced by high doses of the test chemicals, thereby leading to increases in reparative cellular proliferation rates. Recently, we have statistically and mechanistically analyzed the entire 594-study (470 final reports) NTP 2-year rodent cancer database to better understand the conundrum posed by Ames and Gold. Our analysis provides several lines of evidence that support the contention of Ames and Gold. First, across different routes of administration, relatively phylogenetically similar rats and mice are nonetheless discordant for the development of tumors at similar organ sites. Tumor site concordance across sex within species is higher than tumor site concordance across species. Second, many chemicals negative in the Ames test nonetheless induce tumors in either rats or mice. Third, 11 out of 58 chemicals tested by the inhalation route induce lung tumors in mice and not rats, are negative in the Ames test, and exhibit hyperplasia. In 2017, Tomasetti et al. provided evidence for the clinical relevance in humans of the Ames and Gold mechanism regarding amplification of the background mutation rate by demonstrating that the majority of human tumors result from accumulated mutations due to DNA replication errors.

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Section: Introductionmentioning

confidence: 99%

The “false-positive” conundrum in the NTP 2-year rodent cancer study database

Smith

Perfetti²

2018

Toxicology Research and Application

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“…Recently, the QWoE approach has been expanded to assess confidence in potential modes-of-action (MoA) for adverse effects in animal testing, and to assess the human relevance of the best supported MoA (Dekant, 2019). QWoE includes a more detailed assessment of study quality as compared to other evaluation systems such as the Klimisch (Klimisch et al, 1997), SciRAP (Beronius et al, 2018), or general WoE-approaches (Rhomberg et al, 2013a ; 2013b). Moreover, properly designed QWoE may provide a more reliable assessment of the outcome of animal/human studies, the doses/concentrations applied, and the strength and relevance of effects with respect to the hypothesis tested.…”

Section: Quantitative Weight Of Evidencementioning

confidence: 99%

Evaluation of animal toxicity studies with diisocyanates regarding presence of thresholds for induction and elicitation of respiratory allergy by quantitative weight of evidence

Dekant

Colnot²

2022

Toxicol Ind Health

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Animal toxicity studies on diisocyanates were evaluated using quantitative weight of evidence (QWoE) to test the hypothesis that the dose-response curve shows a threshold for the induction and/or elicitation of respiratory sensitization. A literature search identified 59 references that included at least two concentration groups of the diisocyanate and a vehicle-exposed concurrent control in the study design. These studies were subjected to a QWoE-assessment applying scoring criteria for quality and relevance/strength of effects relevant to the selected endpoint of respiratory sensitization. Overall, the studies assessing dose/concentration-response for diisocyanates with the endpoint, respiratory sensitization, were heterogenous regarding study design, animal models used, endpoints assessed, and quality. Only a limited number of the studies subjected to the QWoE-assessment allowed drawing conclusions about possible thresholds for respiratory sensitization. Highest quality and relevance/strength of effects scores were obtained by a series of studies specifically designed to investigate a potential threshold for elicitation of respiratory sensitization in the Brown Norway (BN) rat. These studies applied an elaborate study design to optimize induction of respiratory sensitization and reduce interference by respiratory tract irritation. In summary, the available studies provided moderate to good support for the existence of a threshold for elicitation and limited to moderate support for a threshold regarding induction of respiratory allergy by diisocyanates in experimental animals. However, a quantitative extrapolation of threshold values established in rodents to humans remains complex.

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“…Agents are classified into four groups by the International Agency for Research on Cancer (IARC 2014) as follows (summarized in IARC Table II This grouping is evidence-based (DeSesso and Lavin 2001; Rhomberg et al 2013): the more evidence that is found indicating carcinogenicity, the higher the carcinogen level of a substance. These four groups show the uncertainty of hazard identification.…”

Section: Hazardous Agent Identificationmentioning

confidence: 99%

A Fuzzy Logic Approach to Assess, Manage, and Communicate Carcinogenic Risk

Matbouli

Hipel

Kilgour

et al. 2014

Human and Ecological Risk Assessment: An International Journal

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A prospective approach to addressing carcinogen risk assessment is presented. Fuzzy reasoning is used to assess carcinogenic risk, characterize it, and control it. The approach is inspired by fuzzy control inference that deploys linguistic intelligence as input to a system described numerically through membership functions. Fuzzy-based reasoning to estimate carcinogenic risk provides several advantages as discussed here. The fuzzy reasoning approach has more capabilities than traditional models in dealing with risk agents that are probably carcinogens, possibly carcinogens, not classifiable as carcinogens, and probably not carcinogens. Input-output surfaces are presented for each hazard group to enable fast inferencing. Then, a hypothetical example is given to compare the results of traditional methods and the fuzzy-based approach to estimating the risk of a carcinogen to a human population. Results show similarity in risk characterization with less input information to the fuzzybased approach. Fuzzy reasoning characterizes risk in more explicit and easy to grasp terms. Two outputs of the inferencing system are risk characterization and risk control or remediation.

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The Weight of Evidence Does Not Support the Listing of Styrene as “Reasonably Anticipated to be a Human Carcinogen” in NTP's Twelfth Report on Carcinogens

Cited by 10 publications

References 43 publications

The “false-positive” conundrum in the NTP 2-year rodent cancer study database

The “false-positive” conundrum in the NTP 2-year rodent cancer study database

Evaluation of animal toxicity studies with diisocyanates regarding presence of thresholds for induction and elicitation of respiratory allergy by quantitative weight of evidence

A Fuzzy Logic Approach to Assess, Manage, and Communicate Carcinogenic Risk

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