Search

BACKGROUND: Traditional dose-response assessment applies different low-dose extrapolation methods for cancer and noncancer effects and assumes that all carcinogens are mutagenic unless strong evidence suggests otherwise. Additionally, primarily focusing on one critical effect, dose-response modeling utilizes limited mode of action (MOA) data to inform low-dose risk. OBJECTIVE: We aimed to build a dose-response modeling framework that continuously extends the curve into the low- dose region via a quantitative integration of MOA information and to estimate MOA-based points of departure (PODs) for nonmutagenic carcinogens. METHODS: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was used as an example to demonstrate the new dose-response modeling framework. There were three major steps included: a) identifying and extracting key quantifiable events (KQEs), b) calculating essential doses that sequentially activate KQEs using the benchmark dose (BMD) methodology, and c) characterizing pathway dose-response relationship for MOA- based POD estimation. RESULTS: We identified and extracted six KQEs and corresponding essential events composing the MOA of TCDD-induced liver tumors. With the essential doses estimated from the BMD method using various settings, three link functions were applied to model the pathway dose-response relationship. Given a toxicologically plausible definition of adversity, an MOA-based POD was derived from the pathway dose- response curve. The estimated MOA-based PODs were generally comparable with traditional PODs and can be further used to calculate reference doses (RfDs). CONCLUSIONS: The proposed framework quantitatively integrated mechanistic information in the modeling process and provided a promising strategy to harmonize cancer and noncancer dose-response assessment through pathway dose-response modeling. However, the framework can also be limited by data availability and the understanding of the underlying mechanism. https://doi.org/10.1289/EHP12677, Introduction Chemical risk assessment, a vital tool to protect human and environmental health, has been widely used to evaluate the toxicity of substances by regulatory agencies. (1,2) Recently, in addition [...]

Dieldrin is an organochlorine insecticide that was widely used until 1970 when its use was banned because of its liver carcinogenicity in mice. Several long-term rodent bioassays have reported dieldrin to induce liver tumors in in several strains of mice, but not in rats. This article reviews the available information on dieldrin liver effects and performs an analysis of mode of action (MOA) and human relevance of these liver findings. Scientific evidence strongly supports a MOA based on CAR activation, leading to alterations in gene expression, which result in increased hepatocellular proliferation, clonal expansion leading to altered hepatic foci, and ultimately the formation of hepatocellular adenomas and carcinomas. Associative events include increased liver weight, centrilobular hypertrophy, increased expression of Cyp2b10 and its resulting increased enzymatic activity. Other associative events include alterations of intercellular gap junction communication and oxidative stress. Alternative MOAs are evaluated and shown not to be related to dieldrin administration. Weight of evidence shows that dieldrin is not DNA reactive, it is not mutagenic, and it is not genotoxic in general. Furthermore, activation of other pertinent nuclear receptors, including PXR, PPARα, AhR, and estrogen are not related to dieldrin-induced liver tumors nor is there liver cytotoxicity. In previous studies, rats, dogs, and non-human primates did not show increased cell proliferation or production of pre-neoplastic or neoplastic lesions following dieldrin treatment. Thus, the evidence strongly indicates that dieldrin-induced mouse liver tumors are due to CAR activation and are specific to the mouse, which are qualitatively not relevant to human hepatocarcinogenesis. Thus, there is no carcinogenic risk to humans. This conclusion is also supported by a lack of positive epidemiologic findings for evidence of liver carcinogenicity. Based on current understanding of the mode of action of dieldrin-induced liver tumors in mice, the appropriate conclusion is that dieldrin is a mouse specific liver carcinogen and it does not pose a cancer risk to humans. [ABSTRACT FROM AUTHOR]

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

Perchloroethylene (PCE) is used as a solvent and chemical intermediate. Following chronic inhalation exposure, PCE selectively induced liver tumors in mice. Understanding the mode of action (MOA) for PCE carcinogenesis in mice is important in defining its possible human cancer risk. The proposed MOA is based on the extensive examination of the peer-reviewed studies that have assessed the mouse liver effects of PCE and its major oxidative metabolite trichloroacetic acid (TCA). Similar to PCE, TCA has also been demonstrated to liver tumors selectively in mice following chronic exposure. The Key Events (KE) of the proposed PCE MOA involve oxidative metabolism of PCE to TCA [KE 1]; activation of the peroxisome proliferator-activated receptor alpha (PPARα) [KE 2]; alteration in hepatic gene expression including cell growth pathways [KE 3]; increase in cell proliferation [KE 4]; selective clonal expansion of hepatic preneoplastic foci [KE 5]; and formation of hepatic neoplasms [KE 6]. The scientific evidence supporting the PPARα MOA for PCE is strong and satisfies the requirements for a MOA analysis. The PPARα liver tumor MOA in rodents has been demonstrated not to occur in humans; thus, human liver cancer risk to PCE is not likely. [ABSTRACT FROM AUTHOR]

A main function of dose-response assessment is to estimate a "safe" dose in the target population to support chemical risk assessment. Typically, a "safe" dose is developed differently for cancer and noncancer effects based on a 2-step procedure, ie, point of departure (POD) derivation and low-dose extrapolation. However, the current dose-response assessment framework is criticized for its dichotomized strategy without integrating the mode of action (MOA) information. The objective of this study was, based on our previous work, to develop a MOA-based probabilistic dose-response framework that quantitatively synthesizes a biological pathway in a dose-response modeling process to estimate the risk of chemicals that have carcinogenic potential. 3,3′,4,4′,5-Pentachlorobiphenyl (PCB-126) was exemplified to demonstrate our proposed approach. There were 4 major steps in the new modeling framework, including (1) key quantifiable events (KQEs) identification and extraction, (2) essential dose calculation, (3) MOA-based POD derivation, and (4) MOA-based probabilistic reference dose (RfD) estimation. Compared with reported PODs and traditional RfDs, the MOA-based estimates derived from our approach were comparable and plausible. One key feature of our approach was the use of overall MOA information to build the dose-response relationship on the entire dose continuum including the low-dose region. On the other hand, by adjusting uncertainty and variability in a probabilistic manner, the MOA-based probabilistic RfDs can provide useful insights of health protection for the specific proportion of population. Moreover, the proposed framework had important potential to be generalized to assess different types of chemicals other than nonmutagenic carcinogens, highlighting its utility to improve current chemical risk assessment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Traditional dose–response assessment applies different low-dose extrapolation methods for cancer and noncancer effects and assumes that all carcinogens are mutagenic unless strong evidence suggests otherwise. Additionally, primarily focusing on one critical effect, dose–response modeling utilizes limited mode of action (MOA) data to inform low-dose risk. OBJECTIVE: We aimed to build a dose–response modeling framework that continuously extends the curve into the low-dose region via a quantitative integration of MOA information and to estimate MOA-based points of departure (PODs) for nonmutagenic carcinogens. METHODS: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was used as an example to demonstrate the new dose–response modeling framework. There were three major steps included: a) identifying and extracting key quantifiable events (KQEs), b) calculating essential doses that sequentially activate KQEs using the benchmark dose (BMD) methodology, and c) characterizing pathway dose–response relationship for MOA-based POD estimation. RESULTS: We identified and extracted six KQEs and corresponding essential events composing the MOA of TCDD-induced liver tumors. With the essential doses estimated from the BMD method using various settings, three link functions were applied to model the pathway dose–response relationship. Given a toxicologically plausible definition of adversity, an MOA-based POD was derived from the pathway dose–response curve. The estimated MOA-based PODs were generally comparable with traditional PODs and can be further used to calculate reference doses (RfDs). CONCLUSIONS: The proposed framework quantitatively integrated mechanistic information in the modeling process and provided a promising strategy to harmonize cancer and noncancer dose–response assessment through pathway dose–response modeling. However, the framework can also be limited by data availability and the understanding of the underlying mechanism. [ABSTRACT FROM AUTHOR]

Carbon tetrachloride (CCl4) has been extensively used and reported to produce toxicity, most notably involving the liver. Carbon tetrachloride metabolism involves CYP450-mediated bioactivation to trichloromethyl and trichloromethyl peroxy radicals, which are capable of macromolecular interaction with cell components including lipids and proteins. Radical interaction with lipids produces lipid peroxidation which can mediate cellular damage leading to cell death. Chronic exposure with CCl4 a rodent hepatic carcinogen with a mode of action (MOA) exhibits the following key events: 1) metabolic activation; 2) hepatocellular toxicity and cell death; 3) consequent regenerative increased cell proliferation; and 4) hepatocellular proliferative lesions (foci, adenomas, carcinomas). The induction of rodent hepatic tumors is dependent upon the dose (concentration and exposure duration) of CCl4, with tumors only occurring at cytotoxic exposure levels. Adrenal benign pheochromocytomas were also increased in mice at high CCl4 exposures; however, these tumors are not of relevant importance to human cancer risk. Few epidemiology studies that have been performed on CCl4, do not provide credible evidence of enhanced risk of occurrence of liver or adrenal cancers, but these studies have serious flaws limiting their usefulness for risk assessment. This manuscript summarizes the toxicity and carcinogenicity attributed to CCl4, specifically addressing MOA, dose-response, and human relevance. [ABSTRACT FROM AUTHOR]