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.

Probabilistic risk assessment of occupational exposure to volatile organic compounds in the rendering plant of a poultry slaughterhouse.

In this study, occupational exposure to volatile organic compounds (VOCs) in the rendering plant of poultry slaughterhouse was determined and subsequently, carcinogen and non-carcinogenic risks were assessed using the US Environmental Protection Agency (USEPA). National Institute for Occupational Safety and Health (NIOSH) methods of 1501 and 1600 were used to measure VOCs in the breathing zone of the workers. Samples were analyzed by GC/MS. Carcinogenic and non-carcinogenic risks and sensitivity analysis were carried out using Monte Carlo simulations technique. The concentration of benzene and CS2 was higher than the occupational exposure limits (OEL). The hazard quotient (HQ) values for all measured compounds was more than 1, which indicating the high potential for non-carcinogenic risks. Furthermore, the calculated Lifetime Cancer Risks (LCR) for carcinogenic compounds revealed that cancer risk due to benzene is higher than the maximum acceptable level provided by USEPA (10-6). Based on the sensitivity analysis, the concentration and exposure frequency are the most important variable influencing both carcinogen and non-carcinogenic risks. Therefore, the concentration levels of the VOCs and exposure frequency should be controlled using engineering control measures.

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 µg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication.

An Integrated Experimental Design for the Assessment of Multiple Toxicological End Points in Rat Bioassays.

BACKGROUND: For nearly five decades long-term studies in rodents have been the accepted benchmark for assessing chronic long-term toxic effects, particularly carcinogenicity, of chemicals. The European Food Safety Authority (EFSA) and the World Health Organization (WHO) have pointed out that the current set of internationally utilized test methods capture only some of the potential adverse effects associated with exposures to these agents over the lifetime. OBJECTIVES: In this paper, we propose the adaption of the carcinogenicity bioassay to integrate additional protocols for comprehensive long-term toxicity assessment that includes developmental exposures and long-term outcomes, capable of generating information on a broad spectrum of different end points. DISCUSSION: An integrated study design based on a stepwise process is described that includes the priority end points of the Economic Co-operation and Development and the National Toxicology Program guidelines on carcinogenicity and chronic toxicity and developmental and reproductive toxicity. Integrating a comprehensive set of relevant toxicological end points in a single protocol represents an opportunity to optimize animal use in accordance with the 3Rs (replacement, reduction and refinement). This strategy has the potential to provide sufficient data on multiple windows of susceptibility of specific interest for risk assessments and public health decision-making by including prenatal, lactational, neonatal exposures and evaluating outcomes over the lifespan. CONCLUSION: This integrated study design is efficient in that the same generational cohort of rats used for evaluating long-term outcomes can be monitored in satellite parallel experiments to measure biomarkers and other parameters related to system-specific responses including metabolic alterations and endocrine disturbances. Citation: Manservisi F, Babot Marquillas C, Buscaroli A, Huff J, Lauriola M, Mandrioli D, Manservigi M, Panzacchi S, Silbergeld EK, Belpoggi F. 2017. An integrated experimental design for the assessment of multiple toxicological end points in rat bioassays. Environ Health Perspect 125:289-295; http://dx.doi.org/10.1289/EHP419.

Use of mode of action data to inform a dose-response assessment for bladder cancer following exposure to inorganic arsenic.

In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies.

International Conference on Harmonisation; final recommendation for the revision of the permitted daily exposure for the solvent cumene according to the maintenance procedures for the guidance Q3C Impurities: Residual Solvents; availability. Notice.

The Food and Drug Administration (FDA) is announcing the availability of a final recommendation for the revision of the permitted daily exposure (PDE) for the solvent cumene according to the maintenance procedures for the guidance for industry entitled ``Q3C Impurities: Residual Solvents.'' The recommendation was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

[Improvement of the organization of oncological aid under conditions of specific technogenic load on the population].

Social and economic disbenifits due to mortality from malignant neoplasms were estimated taking into account the losses of man-years of work, mean life expectancy for the sick, losses from temporary disablement and invalidization caused by malignancies, and the cost of oncological aid. The study was based at an area in Uzbekistan subjected to pollution by industrial wastes from an uranium-extracting enterprise. A special purpose-oriented program has been elaborated for the correction of oncological aid currently provided to the workers of the Navoi mining and metallurgical works and the local population. Its implementation resulted in a 13% reduction of standardized mortality from malignant neoplasm in 2004 compared with 1999 and another 24% in 2009. The disbenefit prevented by the reduction of mortality at active ages is estimated at 60,6 mln rubles.

Bayesian derivation of an oral cancer slope factor distribution for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

The tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is classified by the International Agency for Research on Cancer as a Group 1 carcinogen. Cancer risk assessment in humans exposed to TSNAs largely relies on potency values estimated from animal studies, but available cancer potency values for NNK derived from such studies are conflicting. In this analysis, oral cancer slope factors (CSFo) for NNK were derived according to U.S. Environmental Protection Agency guidelines. An animal study in which rats were exposed to NNK in drinking water was selected as the key study. The multistage-cancer model was fit to the tumor incidence data to determine a point of departure for low dose linear extrapolation, using a benchmark response of 10%. CSFo distributions were then computed using Bayesian methods and Monte Carlo simulation. The resultant CSFo point estimate (BMR/BMDL(10)) was 19.2 (mg/kg day)(-1) based on lung tumor data and 12.2 (mg/kg day)(-1) based on pancreatic tumors. The 95th percentiles of the CSFo distributions were 27.3 and 19.3 (mg/kg day)(-1) based on lung and pancreatic tumors, respectively. The approach using Bayesian methods better accounts for the uncertainty inherent in the values generated using input assumptions and provides for a more robust probabilistic dose-response assessment.

European Union bans atrazine, while the United States negotiates continued use.

Atrazine is a common agricultural herbicide with endocrine disruptor activity. There is evidence that it interferes with reproduction and development, and may cause cancer. Although the U.S. Environmental Protection Agency (EPA) approved its continued use in October 2003, that same month the European Union (EU) announced a ban of atrazine because of ubiquitous and unpreventable water contamination. The authors reviewed regulatory procedures and government documents, and report efforts by the manufacturer of atrazine, Syngenta, to influence the U.S. atrazine assessment, by submitting flawed scientific data as evidence of no harm, and by meeting repeatedly and privately with EPA to negotiate the government's regulatory approach. Many of the details of these negotiations continue to be withheld from the public, despite EPA regulations and federal open-government laws that require such decisions to be made in the open.

Corporate corruption of science--the case of chromium(VI).

Corporate infiltration of a panel convened to set standards for chromium(VI) in California, buttressed by the engineered production of dubious "scientific" literature advancing industry's goal, succeeded in skewing the panel's decision to protect industry profits rather than public health. This situation demonstrates the insidious and effective influence of industry on the regulatory process.

Status of occupational cancer in Lithuania.

Because industrialization in Lithuania started only about 50 years ago, occupational cancer is only now becoming an important issue. This article describes the situation of occupational cancer in Lithuania: research, exposures to carcinogens, regulation, and legal practice. Epidemiologic studies of work-related cancers have shown increased risks among cement, textile, and asbestos-cement workers. In 1997, 28% of employed workers in Lithuania were exposed to carcinogens. A legislation system regulating exposures to carcinogens, harmonized with European Directives, has recently been created. In 1995-2003, there were 5,652 new cases of occupational diseases. However, occupational cancers are seriously underdiagnosed--only one case of cancer was diagnosed as occupational. Establishment of a system that would enable diagnosis, certification, and compensation of cases of occupational neoplasms is essential in Lithuania.

Approaches to carcinogenic risk assessment for polycyclic aromatic hydrocarbons: a UK perspective.

This paper reviews the approaches to carcinogenic risk assessment of polycyclic aromatic hydrocarbons (PAHs) in air pollution with emphasis on high potency PAHs such as dibenzo[a,l]pyrene (DB[a,l]P). The potency of DB[a,l]P may be 100-fold greater than benzo[a]pyrene (B[a]P); thus the B[a]P surrogate approach currently used to monitor for compliance with UK air pollution standards may not be appropriate. It is suggested that an approach based on potency equivalency factors (PEFs) could be developed to include highly potent PAHs provided an appropriate reference data set for relevant PAHs using a route acceptable for inhalation risk assessment is selected. Available data suggest that intratracheal administration of low doses of PAHs to rats is likely to simulate the kinetics of inhalation exposure to PAHs in a feasible manner. The use of a measure of total DNA adducts as an endpoint, which correlates well with lung tumourigenicity, would provide surrogate data for setting PEFs without the need for long-term bioassays in rodents. Further, dose-response studies using intratracheal administration of a range of PAHs singly and in combination to assess additivity are required to develop a PEF system for inhalation PEFs derived from DNA adduct measurements.

Controlling lead concentrations in human blood by regulating the use of lead in gasoline.

After having been emitted at maximum rates in the 1960s and 1970s, lead has become less ubiquitous in industrialized countries as a result of increasingly stringent policies to limit the use of this heavy metal as an anti-knock additive in gasoline. Using a detailed reconstruction of lead emissions in Europe (PbE), of the air concentration of lead in Europe (PbC) and repeated measurements of lead concentrations in human blood (PbB) in Germany since about 1980, we have constructed an empirical model that estimates PbB given PbE. This model is used for 2 purposes: i)To estimate PbB levels for the 1960s and 1970s in Germany, when emissions were maximum and monitoring blood levels had not yet begun. It turns out that PbB peak emissions were reaching a mean level, which health officials considered potentially harmful for fetuses and small children. ii) To estimate how PbB levels may have developed if regulations of the use of lead in gasoline had been implemented differently. In case of no or delayed regulations, the model estimates that PbB levels well beyond the critical level would have emerged. Thus, the regulation instituted in Germany since the 1970s has reduced significant health hazards.

Four decades of gasoline lead emissions and control policies in Europe: a retrospective assessment.

Over decades, large amounts of the neurotoxin lead were released into the European environment, mostly from gasoline lead additives. Emissions were growing unabatedly until the 1970s, when a series of regulations on the allowed gasoline lead content were adopted. As a result, in the 1990s most gasoline contained only small amounts of lead. We have examined this case of environmental pollution and regulation, and performed a retrospective assessment of the extent of regional-scale lead pollution and the effects of gasoline lead regulations in Europe. With the help of a regional climate model, NCEP re-analyses, spatially disaggregated lead emissions from road traffic and point sources, and various local data, the airborne pathways and depositions of gasoline lead in Europe since 1958 were reconstructed. It turns out that this approach is successful in describing the time-variable, spatially disaggregated deposition of gasoline lead. Additional data from analyses of concentrations in biota, including plant leaves, mussels and human blood, allows an assessment about the impact of the lead phase-out on the quality of the environment. Demonstrating the success of the lead policies, concentrations in leaves and human blood have steadily declined since the early 1980s. At the same time, the economic repercussions that had been feared did not emerge. Instead, the affected mineral oil and car manufacturing industries in Germany (our case-study) were able to deal with the effort without incurring significant extra costs. We suggest that our method of quantitatively reconstructing and anticipating fluxes and depositions of substances can be applied to other relevant substances as well, such as, for example, Persistent Organic Pollutants, radioactive substances or pollens.

MTBE ambient water quality criteria development: a public/private partnership.

A public/private partnership was established in 1997, under the administrative oversight of the American Petroleum Institute (API), to develop aquatic toxicity data sufficient to calculate ambient water quality criteria for methyl tertiary-butyl ether (MTBE), a gasoline oxygenate. The MTBE Water Quality Criteria Work Group consisted of representatives from private companies, trade associations, and USEPA. Funding was provided by the private entities, while aquatic biological/toxicological expertise was provided by industry and USEPA scientists. This public/private partnership constituted a nonadversarial, cost-effective, and efficient process for generating the toxicity data necessary for deriving freshwater and marine ambient water quality criteria. Existing aquatic toxicity data were evaluated for acceptability, consistent with USEPA guidance, and nineteen freshwater and marine tests were conducted by commercial laboratories as part of this effort to satisfy the federal criteria database requirements. Definitive test data were developed and reported under the oversight of industry study monitors and Good Laboratory Practice standards auditors, and with USEPA scientists participating in advisory and critical review roles. Calculated, preliminary freshwater criteria for acute (Criterion Maximum Concentration) and chronic (Criterion Continuous Concentration) exposure effect protection are 151 and 51 mg MTBE/L, respectively. Calculated, preliminary marine criteria for acute and chronic exposure effect protection are 53 and 18 mg MTBE/L, respectively. These criteria values may be used for surface water quality management purposes, and they indicate that ambient MTBE concentrations documented in U. S. surface waters to date do not constitute a risk to aquatic organisms.

Scrutinizing three trichloroethylene carcinogenicity classifications in the European Union--implications for the risk assessment process.

In this paper, carcinogenicity classifications of the chlorinated solvent trichloroethylene (TCE) made by the European Union Commission Expert Groups in 1976, 1988, and 2001 are scrutinized and alternative classifications are proposed. It is argued that the TCE database at these three points in time could have been interpreted to fulfill the criteria for stricter classifications than those actually made. Implications of this for the classification process are discussed.

A unified approach to risk assessment for cancer and noncancer endpoints based on benchmark doses and uncertainty/safety factors.

A fundamental goal of toxicology is to determine safe levels of human exposure to toxic substances. In the absence of information to establish dose-response relationships at low exposure levels generally experienced by humans, high-dose to low-dose linear extrapolation is generally used for estimating carcinogenic risks and the no-observed-adverse-effect-level divided by uncertainty (safety) factors is widely used for establishing human exposure guidelines for noncancer effects. The basis and impact of this dichotomy is examined and questioned. It is proposed that a unified approach be adopted for establishing human exposure guidelines for both cancer and noncancer endpoints. It is suggested that a lower confidence limit on the dose estimated to produce an excess incidence of adverse health effects in 10% of the individuals in a human study or 10% of the animals in laboratory experiments be used as a point-of-departure. This dose would be divided by appropriate uncertainty factors to establish human exposure guidelines. For severe irreversible adverse health effects we suggest a total default uncertainty factor (divisor) for animal data on the order of 10,000, which is comparable to current guidelines. For reversible biological effects a smaller default uncertainty factor on the order of 1000 may be employed. This is comparable to the divisor often used currently when the point-of-departure is the lowest-observed-adverse-effect-level. It is asserted that the toxicological information generally available does not warrant numerical estimates of risk at low levels of human exposure. Rather, we support a unified approach for all adverse health effects of dividing a benchmark dose by appropriate uncertainty factors to establish guidelines for human exposures to toxic substances.

The Service for the Organization of Postexposure Medical Examinations: ODIN.

In Germany, occupational contact with carcinogenic substances is regulated by very strict legislation. Thus, alongside strict implementation of agreement 139 of the International Labour Organization (ILO), legislation governing the medical monitoring and care of employees in the form of specialist preventive medical examinations is also in force. It is extremely important that medical preventive care should continue after employment involving contact with carcinogenic substances has ceased, since there is often a long delay before occupationally induced carcinosis develops. The German Service for the Organization of Postexposure Medical Examinations (ODIN) was established by the statutory German accident insurance institutions to ensure that early detection examinations continue to be performed into the employee's later life. Such preventive examinations can significantly enhance the success of cancer treatment by detecting malignancy in its early stages. The registration by ODIN of data concerning exposure to hazardous substances also has the function of preserving evidence required for possible compensation claims by victims of occupational illnesses. In the longer term, ODIN data may help us to explain the relationship between exposure to hazardous substances and the incidence of carcinosis.

U.S. Environmental Protection Agency guidelines for carcinogen risk assessment: past and future.

The U.S. Environmental Protection Agency (USEPA) recently proposed new guidelines to update and replace the 1986 USEPA Guidelines for Carcinogen Risk Assessment. Today, there is a better understanding of the variety of modes by which carcinogens can operate that did not exist when the 1986 USEPA guidelines were published. Many laboratories are adding new test protocols in their programs directed at questions concerning the mechanisms of action of carcinogens. In response to the evolving science of carcinogenesis, the new guidelines provide an analytical framework for incorporating all relevant biological information and recognizing a variety of situations regarding cancer risk. In addition, the guidelines are flexible enough to allow consideration of future scientific advances.

Risk assessment of carcinogens in food with special consideration of non-genotoxic carcinogens. Scientific arguments for use of risk assessment and for changing the Delaney Clause specifically.

The document "Risk Assessment of Carcinogens in Food with Special Consideration of Non-Genotoxic Carcinogens" was produced by the International Federation of Societies of Toxicologic Pathologists on the occasion of its triannual meeting in Tours, France, April 23-26, 1995. Subsequently, it was endorsed by the North American Society of Toxicologic Pathologists at its annual meeting in San Diego, CA, USA, June 11-15, 1995. This document was written to address up-to-date risk assessment of carcinogens and anachronisms in the Delaney Clause of the US Federal Food, Drug and Cosmetic Act which have become evident since its enactment in 1958. In the intervening years, major progress has been made in understanding mechanisms of cancer induction and in recognizing causes of human cancer. The Clause in conjunction with its present legal interpretation and implementation does not provide for rational, scientific evaluation of carcinogens. It ignores the fact that the diverse mechanisms now known to underlie cancer increases in rodents exposed to high doses of chemicals are often inapplicable to man. In this regard, current evaluation of chemicals based on the tenets of the Delaney Clause is irrational in many cases. The document presents several examples of chemicals to which humans may be exposed through food and which illustrate the need for science-based risk assessment. Appropriate risk assessment methods are available to provide assurance of negligible risk, and accordingly, it is recommended that the Delaney Clause be rescinded as it has outlived its usefulness. This will enable US governmental agencies to regulate the use of chemicals in foods by using appropriate current scientific methods on a case by case basis within the context of other relevant legislation.