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Propylene dichloride (PDC) is a chlorinated substance used primarily as an intermediate in basic organic chemical manufacturing. The United States Environmental Protection Agency (EPA) is currently evaluating PDC as a high-priority substance under the Toxic Substances Control Act (TSCA). We conducted a systematic review of the non-cancer and cancer hazards of PDC using the EPA TSCA and Integrated Risk Information System (IRIS) frameworks. We identified 12 epidemiological, 16 toxicokinetic, 34 experimental animal, and 49 mechanistic studies. Point-of-contact respiratory effects are the most sensitive non-cancer effects after inhalation exposure, and PDC is neither a reproductive nor a developmental toxicant. PDC is not mutagenic in vivo, and while in vitro evidence is mixed, DNA strand breaks consistently occur. Nasal tumors in rats and lung tumors in mice occurred after lifetime high-level inhalation exposure. Cholangiocarcinoma (CCA) was observed in Japanese print workers exposed to high concentrations of PDC. However, co-exposures, as well as liver parasites, hepatitis, and other risk factors, may also have contributed. The cancer mode of action (MOA) analysis revealed that PDC may act through multiple biological pathways occurring sequentially and/or simultaneously, although chronic tissue damage and inflammation likely dominate. Critically, health benchmarks protective of non-cancer effects are expected to protect against cancer in humans., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Heather Lynch reports financial support was provided by American Chemistry Council. Jordan Kozal reports financial support was provided by American Chemistry Council. Andrew Maier reports financial support was provided by American Chemistry Council. Evan Beckett reports financial support was provided by American Chemistry Council. Rita Schoeny reports financial support was provided by American Chemistry Council. Sarah Brown reports financial support was provided by American Chemistry Council. Rachel Freid reports financial support was provided by American Chemistry Council. Melissa J. Vincent reports financial support was provided by American Chemistry Council., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

As part of a systematic review of the non-cancer and cancer hazards of propylene dichloride (PDC), with a focus on potential carcinogenicity in workers following inhalation exposures, we determined that a mode of action (MOA)-centric framing of cancer effects was warranted. In our MOA analysis, we systematically reviewed the available mechanistic evidence for PDC-induced carcinogenesis, and we mapped biologically plausible MOA pathways and key events (KEs), as guided by the International Programme on Chemical Safety (IPCS)-MOA framework. For the identified pathways and KEs, biological concordance, essentiality of KEs, concordance of empirical observations among KEs, consistency, and analogy were evaluated. The results of this analysis indicate that multiple biologically plausible pathways may contribute to the cancer MOA for PDC, but that the relevant pathways vary by exposure route and level, tissue type, and species; further, more than one pathway may occur concurrently at high exposure levels. While several important data gaps exist, evidence from in vitro mechanistic studies, in vivo experimental animal studies, and ex vivo human tumor tissue analyses indicates that the predominant MOA pathway likely involves saturation of cytochrome p450 2E1 (CYP2E1)-glutathione (GSH) detoxification (molecular initiating event; MIE), accumulation of CYP2E1-oxidative metabolites, cytotoxicity, chronic tissue damage and inflammation, and ultimately tumor formation. Tumors may occur through several subsets of inflammatory KEs, including inflammation-induced aberrant expression of activation-induced cytidine deaminase (AID), which causes DNA strand breaks and mutations and can lead to tumors with a characteristic mutational signature found in occupational cholangiocarcinoma. Dose concordance analysis showed that low-dose mutagenicity (from any pathway) is not a driving MOA, and that prevention of target tissue damage and inflammation (associated with saturation of CYP2E1-GSH detoxification) is expected to also prevent the cascade of processes responsible for tumor formation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jordan S. Kozal reports financial support was provided to Stantec (ChemRisk) by American Chemistry Council. Heather N. Lynch reports financial support was provided to Stantec (ChemRisk) by American Chemistry Council. Andy Maier reports financial support was provided to Stantec (ChemRisk) by American Chemistry Council. Rita S. Schoeny reports financial support was provided to Rita Schoeny, LLC by American Chemistry Council. Joanna Klapacz reports a relationship with The Dow Chemical Company that includes: employment. Paul A. Jean reports a relationship with Olin Corporation that includes: employment. Jordan S. Kozal, Heather N. Lynch, and Andy Maier are employees of Stantec (ChemRisk), and Rita S. Schoeny is an independent consultant at Rita Schoeny, LLC; both firms provide services to clients such as governments, corporations, law firms and various scientific/professional organizations. Joanna Klapacz is an employee of The Dow Chemical Company and Paul A. Jean is an employee of Olin Corporation, both producers of PDC. The content and the conclusions of the manuscript are exclusively those of the authors. This manuscript was supported by funding from the American Chemistry Council, an industry trade association., (Copyright © 2023. Published by Elsevier B.V.)

Several exposure limits for perchlorate have been developed based on an early key event, inhibition of radioactive iodide uptake (RAIU) by the thyroid. These assessments have used a variety of definitions of the point of departure. The current assessment revisited the modeling for inhibition of RAIU, using state of the science methods. Bayesian hierarchical modeling was used to account for the repeated measures on the same individuals in the key dataset, and the underlying Beta distribution used for the modeling correctly reflected the bounding of RAIU between 0 and 1. We defined the BMR as a point value of 8% RAIU (rather than a change in RAIU), based on descriptions in the medical literature that RAIU below this value is considered abnormal. Because a definition of the BMR based on the mean response would correspond to about 50% of the population with a response below the BMR at the benchmark dose, we used a hybrid definition of the BMR. That is, the BMD was defined as the dose at which it was estimated that there would be a 10% extra risk in the population of having RAIU of 8% or lower. The resulting point of departure based on the BMDL was 0.03 mg/kg-day., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was supported by Specialised Nutrition Europe (SNE), Brussels, Belgium. The sponsor reviewed a much earlier version of this work, in which the average results from Greer et al. (2002) were modeled using a variety of approaches. However, the sponsor did not see any of the results with the modeling of the individual data from the Greer study prior to submittal of the manuscript. LTH and BCA also have had two recent projects supported by organizations with membership lists that overlap with that of SNE. LTH and BCA received support from Grocery Manufacturers Association, the Institute of Shortening and Edible Oils, the EU Vegetable Oil & Proteinmeal Industry, the Infant Nutrition Council of America, FoodDrink Europe, and the International Technical Caramel Association for a review of benchmark dose modeling methods that was published in 2018. LTH and BCA are also currently receiving support from ILSI NA for an unrelated project., (Copyright © 2021. Published by Elsevier B.V.)

Over 50 years, we have learned a great deal about the biology that underpins cancer but our approach to testing chemicals for carcinogenic potential has not kept up. Only a small number of chemicals has been tested in animal-intensive, time consuming, and expensive long-term bioassays in rodents. We now recommend a transition from the bioassay to a decision-tree matrix that can be applied to a broader range of chemicals, with better predictivity, based on the premise that cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from sustained cell proliferation. The first step is in silico and in vitro assessment for mutagenic (DNA reactive) activity. If mutagenic, it is assumed to be carcinogenic unless evidence indicates otherwise. If the chemical does not show mutagenic potential, the next step is assessment of potential human exposure compared to the threshold for toxicological concern (TTC). If potential human exposure exceeds the TTC, then testing is done to look for effects associated with the key characteristics that are precursors to the carcinogenic process, such as increased cell proliferation, immunosuppression, or significant estrogenic activity. Protection of human health is achieved by limiting exposures to below NOEALs for these precursor effects. The decision tree matrix is animal-sparing, cost effective, and in step with our growing knowledge of the process of cancer formation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Developments in the understanding of the etiology of cancer have profound implications for the way the carcinogenicity of chemicals is addressed. This paper proposes a unified theory of carcinogenesis that will illuminate better ways to evaluate and regulate chemicals. In the last four decades, we have come to understand that for a cell and a group of cells to begin the process of unrestrained growth that is defined as cancer, there must be changes in DNA that reprogram the cell from normal to abnormal. Cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from cell proliferation especially if sustained. Chemicals that act via direct interaction with DNA can induce cancer because they cause mutations which can be carried forward in dividing cells. Chemicals that act via non-genotoxic mechanisms must be dosed to maintain a proliferative environment so that the steps toward neoplasia have time to occur. Chemicals that induce increased cellular proliferation can be divided into two categories: those which act by a cellular receptor to induce cellular proliferation, and those which act via non-specific mechanisms such as cytotoxicity. This knowledge has implications for testing chemicals for carcinogenic potential and risk management., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Developments in the understanding of the etiology of cancer have undermined the 1970s concept that chemicals are either "carcinogens" or "non-carcinogens". The capacity to induce cancer should not be classified in an inflexible binary manner as present (carcinogen) or absent (non-carcinogen). Chemicals may induce cancer by three categories of mode of action: direct interaction with DNA or DNA replication including DNA repair and epigenetics; receptor-mediated induction of cell division; and non-specific induction of cell division. The long-term rodent bioassay is neither appropriate nor efficient to evaluate carcinogenic potential for humans and to inform risk management decisions. It is of questionable predicitiveness, expensive, time consuming, and uses hundreds of animals. Although it has been embedded in practice for over 50 years, it has only been used to evaluate less than 5% of chemicals that are in use. Furthermore, it is not reproducible because of the probabilisitic nature of the process it is evaluating combined with dose limiting toxicity, dose selection, and study design. The modes of action that lead to the induction of tumors are already considered under other hazardous property categories in classification (Mutagenicity/Genotoxicity and Target Organ Toxicity); a separate category for Carcinogenicity is not required and provides no additional public health protection., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Classification schemes for carcinogenicity based solely on hazard-identification such as the IARC monograph process and the UN system adopted in the EU have become outmoded. They are based on a concept developed in the 1970s that chemicals could be divided into two classes: carcinogens and non-carcinogens. Categorization in this way places into the same category chemicals and agents with widely differing potencies and modes of action. This is how eating processed meat can fall into the same category as sulfur mustard gas. Approaches based on hazard and risk characterization present an integrated and balanced picture of hazard, dose response and exposure and allow informed risk management decisions to be taken. Because a risk-based decision framework fully considers hazard in the context of dose, potency, and exposure the unintended downsides of a hazard only approach are avoided, e.g., health scares, unnecessary economic costs, loss of beneficial products, adoption of strategies with greater health costs, and the diversion of public funds into unnecessary research. An initiative to agree upon a standardized, internationally acceptable methodology for carcinogen assessment is needed now. The approach should incorporate principles and concepts of existing international consensus-based frameworks including the WHO IPCS mode of action framework., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Quantitative estimates of cancer risk generally involve low-dose extrapolation based on an exponential dose-response model for dichotomous response data. Frequently more than one data set is available. If a careful analysis of the biological issues indicates that more than one of the available data sets could be used in the quantitative estimate of cancer risk, it is reasonable to think of combining the data. Before combining data, however, it would be prudent to test whether the data sets are compatible with a common dose-response model. If they are not, it could be concluded that an underlying biological factor is responsible. If they are statistically compatible, the decision to combine data sets based on biological issues would be reinforced. A statistical test based on the generalized likelihood ratio method is proposed for evaluating the compatibility of different data sets with a common dose-response model. This method of constructing a statistical test and the associated asymptotic theory is consistent with the approach used by GLOBAL86 (R. B. Howe, K. S. Crump, and C. Van Landingham, GLOBAL86: A Computer Program to Extrapolate Quantal Animal Toxicity Data to Low Doses, K. S. Crump & Co., Ruston, LA, 1986) for estimating the confidence limits that are used as a basis for quantitative estimates.

Quantitative risk assessments for carcinogens conducted by the U.S. EPA have most frequently been based on results of a bioassay from a single sex/strain/species of animal. In some cases, more than one data set derived from different sexes, strains, or species of animals is suitable for quantitative risk assessment. When there is no apparent difference among the data sets in sensitivity to the carcinogen, use of more of the available data should result in a higher level of confidence in the risk estimate. Several biological factors must be considered before combining data from different animal sexes, strains, species, or tumor sites. The relevance of the animal models, study design and execution, dose selection, and route of administration are factors which influence whether data from separate studies should be combined. The decision to combine data sets is also based on what is known of the mechanism of action of the agent, its pharmacokinetics, any species/sex specificity of the effect, and considerations regarding tumor site specificity. Statistical analysis also indicates whether the data sets may be described by the same multistage model. The evaluation of these factors in the decision to combine or not combine data sets is discussed.

A polychlorinated biphenyl mixture, Aroclor 1254, two commercial grade insecticides, mirex and kepone, and a pesticide breakdown product, 1,2,4-trichlorobenzene were evaluated for mutagenicity and hepatic enzyme induction potential in the Salmonella/microsomal assay. None was found to revert strains TA1535, TA1537, TA98 or TA100 when tested with or without metabolic activation. Liver microsomal extracts (S9) from rats induced with 1,2,4-trichlorobenzene were shown to differ from S9 of either control or Aroclor 1254-induced rats in the capacity to activate 2-aminoanthracene mutagenesis.