Annual Meeting of the Japanese Society of Toxicology

The IARC Monographs identify causes of cancer in the human environment, including chemicals, mixtures, personal habits, drugs, biological and physical agents. Since its inception in 1971 the Monographs programme has evaluated over 950 agents, with more than 100 classified as carcinogenic to humans and over 300 as probably or possibly carcinogenic to humans. The process of causal inference used for IARC’s evaluations is laid out in the Preamble to the Monographs. International Working Groups of invited experts evaluate human, animal and mechanistic evidence and reach a consensus evaluation of carcinogenicity for each agent. First, human and animal cancer data are evaluated separately, with the weight of the evidence for causation being categorised as Sufficient, Limited, Inadequate, or Suggesting lack of carcinogenicity. For the overall evaluation of carcinogenicity, the Working Group considers the totality of the evidence and assigns agents to one of 5 causal groups: 1 Carcinogenic to Humans; 2A Probably carcinogenic to humans; 2B Possibly carcinogenic to humans; 3 Not classifiable as to carcinogenicity to humans, or 4 Probably not carcinogenic to humans. Mechanistic evidence has an increasing role in overall evaluations; it can be invoked to upgrade an evaluation, or, alternatively, strong mechanistic evidence for the absence of a relevant mechanism in humans can downgrade an evaluation based on animal cancer data. The Monographs’ evaluations constitute hazard identification, but the Preamble has scope for characterising risk quantitatively. The presentation will give an overview on strategic directions of the Monographs programme and use some recent evaluations to illustrate procedures.

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Translating nonclinical data and observations into possible clinical outcomes can make the drug development process more efficient and cost-effective. Additionally, translation allows a better understanding of drug toxicities and human relevance, which aligns with the heightened regulatory emphasis on the delivery of safer medicines with fewer side effects. Despite enhanced efforts to understand and derisk targets for potential safety issues, cardiovascular toxicity, hepatotoxicity, and nephrotoxicity continue to halt clinical trial progression and contribute to post-marketing withdrawals of new medicines. Even areas of expected high translation from preclinical to clinical outcomes such as hematotoxicity continue to cause > 10% clinical attrition. This presentation will focus on translatability of biomarkers and models in these four high areas of attrition and highlight new models and assays that may enhance translation. Safety risks associated with other target organs occur less frequently, but also remain problematic in drug development. A few examples of exploratory preclinical models in areas that demonstrate known gaps in translation, such as testes toxicology, will also be covered. Translation of preclinical toxicology findings remains pivotal in drug development. It allows us to answer two key questions surrounding the relevance of preclinical results: (1) How can we guard against drug-induced injuries seen in the clinical but not in preclinical toxicology and (2) How can we continue to advance development of good drugs that show toxicity in animals that are not expected to be present or relevant in humans?

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Recent changes in regulatory policy have mandated that all new pharmaceuticals be evaluated for the potential for abuse. These changes have largely come about in response to increases in overdose deaths noted in the US primarily, but also in other geographic regions. The evaluation of abuse potential can be as simple as a careful assessment of brain penetration of the drug, defining secondary pharmacology, in addition to an understanding if the drug produces behavioral effects in preclinical species as well as in clinical trials. If signals for central nervous system activity are noted, a series of assays, can be employed to better understand whether the new drug produces effects similar to know drugs of abuse, is rewarding when it is administered, and whether repeated administration of the drug will produce physical dependence – characterized by a withdrawal syndrome. The assay for detecting similarity to known drugs of abuse is a Drug Discrimination Assay, in which animals a trained to detect whether they have been administered drugs. For measuring rewarding effects, IV self- administration procedures can be employed, and specific tests for physical dependence are conducted. If indications of abuse potential are noted in the preclinical assays, implementation of human clinical trials to address abuse potential may occur. These assays will be described in detail in the current lecture, enhanced by examples from the scientific literature.

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Previous studies have demonstrated that methylphenidate, MDMA (3,4-methylenedioxymethamphetamine), and other psychostimulants exert stimulant-like subjective effects in humans. Furthermore, MDMA and methylphenidate substitute for the discriminative stimulus effects of psychostimulants, such as amphetamine and cocaine, in animals, which suggests that MDMA and methylphenidate may produce similar discriminative stimulus effects in rats. However, there is no evidence regarding the similarities between the discriminative stimulus effects of MDMA and methylphenidate. To explore this issue, cross-substitution, substitution, and combination tests were conducted in rats that had been trained to discriminate between MDMA (2.5 mg/kg) or methylphenidate (5.0 mg/kg) and saline. In the cross-substitution tests, MDMA and methylphenidate did not cross-substitute for each other. In the substitution test, methamphetamine substituted for the discriminative stimulus effects of methylphenidate, but not for those of MDMA. Furthermore, ephedrine and bupropion, which activate dopaminergic and noradrenergic systems, substituted for the discriminative stimulus effects of methylphenidate. On the other hand, serotonin (5-HT) receptor agonists 5-HT1A and 5-HT2 fully substituted for the discriminative stimulus effects of MDMA. These results suggest that activation of the noradrenergic and dopaminergic systems is important for the discriminative stimulus effects of methylphenidate, whereas activation of the serotonergic system is crucial for the discriminative stimulus effects of MDMA. Even though MDMA, like psychostimulants, exerts stimulant-like effects, our findings clearly indicate that the discriminative stimulus effects of MDMA are distinctly different from those of other psychostimulants in rats.

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