The Toxicological Basis of Threshold Limit Values: 2. Pathological and Biochemical Criteria

Rowe, V. K.; Wolf, Mirela; Weil, Carl; Smyth, Henry F.

doi:10.1080/00028895909343730

Cited by 15 publications

(3 citation statements)

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“…Drug and chemically induced liver enlargement in subchronic and chronic toxicology studies in rodents has, for many years, taxed the toxicology profession in terms of its perceived relevance to hepatotoxicity, to carcinogenicity in lifetime bioassays at similar dose levels, and in terms of its relevance to man (Cohen and Grasso 1981; Elcombe, Rose, and Pratt 1985; Grasso and Hinton 1991). The fact that after more than 50 years of debate (Gilbert and Golberg 1965; Rowe et al 1959; Weil and McCollister 1963) the issue remains as contentious as ever prompted the European Society of Toxicologic Pathology (ESTP) to convene an expert opinion group to discuss the current state of the science. The purpose of the workshop was to discuss the significance of hepatocellular hypertrophy in rodents, define more clearly when adaptive responses become adverse, and understand the long-term consequences of hepatocellular hypertrophy in order to guide scientific opinion for risk assessment in man and dose setting for longer term animal studies.…”

Section: Introductionmentioning

confidence: 99%

“…The fact that after more than 50 years of debate (Gilbert and Golberg 1965;Rowe et al 1959;Weil and McCollister 1963) the issue remains as contentious as ever prompted the European Society of Toxicologic Pathology (ESTP) to convene an expert opinion group to discuss the current state of the science. The purpose of the workshop was to discuss the significance of hepatocellular hypertrophy in rodents, define more clearly when adaptive responses become adverse, and understand the long-term consequences of hepatocellular hypertrophy in order to guide scientific opinion for risk assessment in man and dose setting for longer term animal studies.…”

Section: Introductionmentioning

confidence: 99%

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Liver Hypertrophy

Elcombe²,

et al. 2012

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Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARa. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Liver Hypertrophy

Elcombe²,

et al. 2012

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“…‘DC 200 fluids’ (viscosity 350 centistokes (See Appendix F for information on the test material)) was reported to be of low acute oral toxicity in rats (Rowe et al., 1948 ).…”

Section: Assessmentmentioning

confidence: 99%

Re‐evaluation of dimethyl polysiloxane (E 900) as a food additive

Younes¹,

Aquilina²,

Castle³

et al. 2020

EFS2

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The Panel on Food Additives and Flavourings (FAF) provided a scientific opinion re-evaluating the safety of dimethyl polysiloxane (E 900) as a food additive. E 900 was evaluated by the Scientific Committee on Food (SCF) in 1990 and agreed with the Acceptable Daily Intake (ADI) of 1.5 mg/kg body weight (bw) per day previously established by Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1974. Dimethyl polysiloxane was only absorbed to a very limited extent from the gastrointestinal tract following oral administration and the vast majority was excreted unchanged in the faeces. Corneal opacities and other effects on cornea were observed in studies in rats. These effects are considered to be caused by direct contact with the test substance in the feed and/or with the test substance in the faeces and not due to systemic exposure. The Panel considered that oral exposure of dimethyl polysiloxane did not result in any systemic adverse effects in any species and dose tested and there is no concern with respect to genotoxicity of dimethyl polysiloxane (E 900). From a 26-month toxicity study in rats, a No Observed Adverse Effect Level (NOAEL) of 1,742 and 2,055 mg dimethyl polysiloxane/kg bw per day for female and male, respectively, was identified. Using the NOAEL 1,742 mg/kg bw per day, the Panel established an ADI of 17 mg/kg bw per day for E 900 by applying an uncertainty factor of 100. Accordingly, the ADI for dimethyl polysiloxane (E 900) of 1.5 mg/kg bw per day, established by SCF in 1990, is withdrawn. The exposure estimates for the different population groups of all exposure scenarios did not exceed the ADI of 17 mg/kg bw per day for E 900. The Panel concluded that there is not a safety concern at the reported uses and use levels for dimethyl polysiloxane (E 900). The Panel also proposed a number of recommendations for the EU specifications to be amended.

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The History and Biological Basis of Occupational Exposure Limits for Chemical Agents

Paustenbach¹

2001

Patty's Industrial Hygiene

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Over the past 60 years, many organizations in numerous countries have proposed occupational exposure limits (OELs) for airborne contaminants (1). The limits or guidelines that have been the most widely accepted both in the United States and in most other countries are those issued annually by the American Conference of Governmental Industrial Hygienists (ACGIH) and are termed Threshold Limit Values Ò (TLVs) (1-10).The usefulness of establishing OELs for potentially harmful agents in the working environment has been demonstrated repeatedly since their inception (3, 5, 6). It has been claimed that whenever these limits have been implemented in a particular industry, no worker has been shown to have sustained serious adverse effects on his health as a result of exposure to these concentrations of an industrial chemical (7). Although this statement is arguable with respect to the acceptability of OELs for those chemicals established before 1980, and later found to be carcinogenic, there is little doubt that millions of persons have avoided serious effects of workplace exposure due to their existence.

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The Toxicological Basis of Threshold Limit Values: 2. Pathological and Biochemical Criteria

Cited by 15 publications

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Liver Hypertrophy

Liver Hypertrophy

Re‐evaluation of dimethyl polysiloxane (E 900) as a food additive

The History and Biological Basis of Occupational Exposure Limits for Chemical Agents

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