An evolution of risk assessment for potential carcinogens in food: Scientific session proceedings.

Modern perspectives on the risk assessment of carcinogenic potential of chemicals have taken shape within the last two decades. This has been due to both developments in the understanding of the biology and etiology of cancer and by advances in in silico and in vitro assays. Moving away from a conventional binary carcinogen/non-carcinogen model, modern frameworks offer more nuanced classification structures based on the understanding of mechanisms involved or potentially involved in rodent carcinogenicity. Given these developments, a scientific session at the 2020 Winter Meeting of the Toxicology Forum was organized to explore the impact these innovative approaches will have on food safety assessments and what considerations should be addressed in developing a new carcinogenic risk assessment approach for substances in foods. The session reviewed challenges faced by food toxicologists and risk assessors, current standard approaches for evaluating carcinogenic risk of food substances, limitations of these standard approaches, and potential methods to implement next generation assays and modern carcinogenic frameworks into food safety assessments. Current perspectives of US regulatory, industry, and academic stakeholders were represented during speaker presentations and a moderated Panel Discussion. This Workshop Report provides an overview of key themes and information presented during the session. Summary statements were prepared by the authors and reviewed by the presenters but do not necessarily represent the position or policy of the FDA, the EPA, or other affiliations.

A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens.

Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice. To address this risk assessment need, a committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute conducted a multisector workshop in late 2009 to discuss available literature, different methodologies, and a proposed framework. The proposed framework provides a decision tree and guidance for cancer risk assessments for less-than-lifetime exposures based on current knowledge of mode of action and dose-response. Available data from rodent studies and epidemiological studies involving less-than-lifetime exposures are considered, in addition to statistical approaches described in the literature for evaluating the impact of changing the dose rate and exposure duration for exposure to carcinogens. The decision tree also provides for scenarios in which an assumption of potential carcinogenicity is appropriate (e.g., based on structural alerts or genotoxicity data), but bioassay or other data are lacking from which a chemical-specific cancer potency can be determined. This paper presents an overview of the rationale for the workshop, reviews historical background, describes the proposed framework for assessing less-than-lifetime exposures to potential human carcinogens, and suggests next steps.

A weight of evidence assessment of the genotoxic potential of 4-methylimidazole as a possible mode of action for the formation of lung tumors in exposed mice.

4-Methylimidazole (4-MeI) is a byproduct formed during the cooking of foods containing carbohydrates and amino acids, including the production of flavors and coloring substances, e.g., class III and IV caramel colors, used in many food products with extensive human exposure. Two-year rodent bioassays via oral exposure conducted by the National Toxicology Program reported evidence of carcinogenicity only in B6C3F1 mice (increased alveolar/bronchial neoplasms). In 2011, the International Agency for Research on Cancer classified 4-MeI as Group 2B, "possibly carcinogenic to humans". An expert panel was commissioned to assess the genotoxic potential of 4-MeI and the plausibility of a genotoxic mode of action in the formation of lung tumors in mice when exposed to high doses of 4-MeI. The panel defined and used a weight-of-evidence (WOE) approach that included thorough evaluation of studies assessing the genotoxic potential of 4-MeI. The panelists categorized each study, consisting of study weight, degree of technical performance, study reliability, and contribution to the overall WOE. Based on the reviewed studies' weighted contribution, the panel unanimously concluded that the WOE supports no clear evidence of in vivo genotoxicity of 4-MeI and no association for a genotoxic mode of action in the formation of mouse lung tumors.

Refining the threshold of toxicological concern (TTC) for risk prioritization of trace chemicals in food.

Due to ever-improving analytical capabilities, very low levels of unexpected chemicals can now be detected in foods. Although these may be toxicologically insignificant, such incidents often garner significant attention. The threshold of toxicological concern (TTC) methodology provides a scientifically defensible, transparent approach for putting low-level exposures in the context of potential risk, as a tool to facilitate prioritization of responses, including potential mitigation. The TTC method supports the establishment of tiered, health-protective exposure limits for chemicals lacking a full toxicity database, based on evaluation of the known toxicity of chemicals which share similar structural characteristics. The approach supports the view that prudent actions towards public health protection are based on evaluation of safety as opposed to detection chemistry. This paper builds on the existing TTC literature and recommends refinements that address two key areas. The first describes the inclusion of genotoxicity data as a way to refine the TTC limit for chemicals that have structural alerts for genotoxicity. The second area addresses duration of exposure. Whereas the existing TTC exposure limits assume a lifetime of exposure, human exposure to unintended chemicals in food is often only for a limited time. Recommendations are made to refine the approach for less-than-lifetime exposures.

The Occurrence of Aflatoxin in Peanut Butter From 1982 to 1989.

Randomly chosen, commercially available, market basket samples of on-the-shelf brands of peanut butter were routinely tested for the presence of aflatoxin from 1982 to 1989. Standard analytical procedures were employed which included high performance liquid chromatography and thin layer chromatography. During the eight years studied, 74% of the samples were positive for the presence of aflatoxin. Of those samples testing positive which excluded no detect samples or "zero values", 8.6% were found to be contaminated between 20 and 50 ppb, 3.7% were between 50 and 100 ppb, and 2.2% were above 100 ppb. The total for this evaluation approach was 14.5%. When all samples including nondetectable were considered, only 9.8% of 2510 samples exceeded the U.S. Food and Drug Administration action level for total aflatoxin. With the exception of 1986 and 1987, aflatoxin levels in commercially available peanut butter offered for sale to the public in this particular state have been well controlled. It is a monitoring effort such as this, conducted as checks on the final product on sale to the public, that provides the final line to protect public health from exposure to mycotoxins. Based on these regional data for an eight-year period reported herein, it is apparent that the findings could be used in conjunction with other regional and national studies to support a reduction of the 20 ppb U.S. action level.