Sir Colin Berry

Toxicology and epidemiology: Improving the science with a framework for combining toxicological and epidemiological evidence to establish causal inference

Historically, toxicology has played a significant role in verifying conclusions drawn on the basis of epidemiological findings. Agents that were suggested to have a role in human diseases have been tested in animals to firmly establish a causative link. Bacterial pathogens are perhaps the oldest examples, and tobacco smoke and lung cancer and asbestos and mesothelioma provide two more recent examples. With the advent of toxicity testing guidelines and protocols, toxicology took on a role that was intended to anticipate or predict potential adverse effects in humans, and epidemiology, in many cases, served a role in verifying or negating these toxicological predictions. The coupled role of epidemiology and toxicology in discerning human health effects by environmental agents is obvious, but there is currently no systematic and transparent way to bring the data and analysis of the two disciplines together in a way that provides a unified view on an adverse causal relationship between an agent and a disease. In working to advance the interaction between the fields of toxicology and epidemiology, we propose here a five-step “Epid-Tox” process that would focus on: (1) collection of all relevant studies, (2) assessment of their quality, (3) evaluation of the weight of evidence, (4) assignment of a scalable conclusion, and (5) placement on a causal relationship grid. The causal relationship grid provides a clear view of how epidemiological and toxicological data intersect, permits straightforward conclusions with regard to a causal relationship between agent and effect, and can show how additional data can influence conclusions of causality.

Thiazopyr and thyroid disruption: case study within the context of the 2006 IPCS Human Relevance Framework for analysis of a cancer mode of action.

Thiazopyr increases the incidence of male rat thyroid follicular-cell tumors; however, it is not carcinogenic in mice. Thiazopyr is not genotoxic. Thiazopyr exerts its carcinogenic effect on the rat thyroid gland secondary to enhanced metabolism of thyroxin leading to hormone imbalance. The relevance of these rat tumors to human health was assessed by using the 2006 IPCS Human Relevance Framework. The postulated rodent tumor mode of action was tested against the Bradford Hill criteria and was found to satisfy the conditions of dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity that fits with a well-established mode of action for thyroid follicular-cell tumors. Although the postulated mode of action could theoretically operate in humans, marked quantitative differences in the inherent susceptibility for neoplasia to thyroid hormone imbalance in rats allows for the conclusion that thiazopyr does not pose a carcinogenic hazard to humans.

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment

Abstract The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is “probably carcinogenic to humans” (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC’s assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies. Two of the Panels (animal bioassay and genetic toxicology) also provided a critique of the IARC position with respect to conclusions made in these areas. The incidences of neoplasms in the animal bioassays were found not to be associated with glyphosate exposure on the basis that they lacked statistical strength, were inconsistent across studies, lacked dose-response relationships, were not associated with preneoplasia, and/or were not plausible from a mechanistic perspective. The overall weight of evidence from the genetic toxicology data supports a conclusion that glyphosate (including GBFs and AMPA) does not pose a genotoxic hazard and therefore, should not be considered support for the classification of glyphosate as a genotoxic carcinogen. The assessment of the epidemiological data found that the data do not support a causal relationship between glyphosate exposure and non-Hodgkin’s lymphoma while the data were judged to be too sparse to assess a potential relationship between glyphosate exposure and multiple myeloma. As a result, following the review of the totality of the evidence, the Panels concluded that the data do not support IARC’s conclusion that glyphosate is a “probable human carcinogen” and, consistent with previous regulatory assessments, further concluded that glyphosate is unlikely to pose a carcinogenic risk to humans.

Reproducibility in experimentation – the implications for regulatory toxicology

A paper based on the Sir William Paton lecture of the British Society of Toxicology, 2014. Sir William Patons classical exploitation of nitrogen in mixtures of gases for deep-sea diving is a good example of what would now be called “blue skies” research where the data obtained were used as the basis for subsequent hypothesis-driven work. Like his work on acetyl choline, the original observations were the basis for further painstaking and step-like progression by experimentation, where each I was dotted and T crossed as the establishment of a therapy or practice was built into a clinical framework or workplace. However, in recent times there has been a failure to follow a similar cautious and pragmatic practice of advancement of knowledge at the interface of Science and Policy. Inadequately investigated associations are made the basis of speculative therapeutic or dietary interventions in frameworks where lack of effect is often not demonstrable and where the possibility of harm is seldom considered, notably in the dietary field. In the same way, isolated findings in regulatory studies may lead to poor decision making or to extensive work to explain non-significant events. The Economist has pointed out that venture capitalists use the rule that only 50% of academic study results can be replicated and Begley and Ellis report that a study of 53 “landmark” papers in Oncology found that only 6 were reproducible even with co-operation of the original authors. So what notice should be taken of single adverse toxicological studies in animals? Of isolated, epidemiologically determined associations? What is the scientific value of an individual regulatory study? What is the probability of error? What is the role of chance and variation? Only an understanding of mechanisms of production of the effect in question can resolve these issues.

Whither the impending european regulation of presumed endocrine disruptors

The legislative impulse to regulate presumed endocrine disrupting chemicals (EDCs) was born as an appendage to the US Food Quality Protection Act of 1996, focusing on public health rather than environmental issues. Pressed by advocacy claims, US legislators were persuaded by a study in animals shortly after officially labeled as scientific misconduct1 and by epidemiologic claims that could not be validated. Twenty years later, the momentum to regulate EDCs has spread worldwide, even though many studies over the last decades have yet to yield credible epidemiologic evidence of public health adversities linked to xenoendocrine contaminants. Absent a confirmed public health target, what could justify a program to regulate presumed EDCs? The European Commission in June 2016 issued draft criteria for EDCs identification and regulation, still set in the conjectural frameworks of regulatory science and precautionary considerations.2 Animal and reductionist laboratory tests are to be used because tests in humans are not possible, and arbitrary definitions of adverse effects are to be adopted as valid clinical proxies for humans. As a novel challenge, the drafted criteria disregard potency in identifying EDC hazards, contrary to plain empirical evidence, common sense and elementary thermodynamics. Clearly, without sufficient causal potencies nothing stirs in the natural universe, including endocrine-dependent events. A group of experts hosted by the German Federal Institute for Risk Assessment (BfR), included potency in the identification of EDC hazards and proposed that any substance could be considered an EDC, if acting by an endocrine mode of action (MoA) and causing adverse effects in a daily dose range up to1000 mg/Kg bw.3 The equivalent upper dose would be 70g daily for a 70 Kg person. On these grounds, and invoking precaution, regulators likely would prescribe the highest doses as the standard for EDC testing, parallel to the prescribed maximum tolerated dose (MTD) for carcinogen bioassays. Such a testing regimen would likely indict numerous substances, even though typical xenoendocrines show receptor binding affinities thousands of times lower than human physiologic hormones, and are commonly experienced at very low concentrations. A regulatory scheme on these terms would considerably reduce vegetal food supplies by banning a large segment of staple foods that carry low levels of phytoestrogens. It would also ban many cosmetics, medicines and other compounds containing low levels of natural and synthetic hormones. With these prospects, and conceding that regulation of putative EDCs may not be resisted, the adoption of pertinent World Health Organization (WHO/IPCS) testing guidelines has been considered.4 Excluding reductionist laboratory assays, the guidelines endorse tests in appropriate whole animal models to reach estimates of potencies and NOAELs against human hormone standards. On this evidence, it would be questionable to estimate human risks in the absence of clinical epidemiologic benchmarks, but it would be sensible to exonerate and remove from public anxieties those substances testing positive below appropriate thresholds of toxicologic or regulatory concern (TTC/TRC), at realistic exposures. Substances exceeding those thresholds would be regulated, although few of such instances could likely be found, due to the absence of clinical epidemiologic signals and the low concentrations and receptor binding affinities of putative xenoendocrines. Opposing such options, a European EDC regulatory program disregarding potency would reinforce a dangerous precedent by further encouraging the creative regulation of putative hazards for putative public health adversities. The Commission did ask for public comments on the drafted criteria, but the first question is why the Commission chose to embark on this course. Is the Commission intrigued by the prospect of a new open season of authoritarian regulations justified by the flimsiest conjectures? Does the Commission hope for a flood of protests to counteract advocacy pressures, and thus to reinstate potency as a core justification of EDCs regulation? Potency or no potency, however, EDC regulation in Europee and similarly worldwide e is posed to continue in an autocratic rather than factual mode: it will be set by the same administrators writing rules, policing, prosecuting, judging, and penalizing. They also will appoint juries of advisors, selected by conflict of interest criteria 1 Office of Research Integrity, US National Institutes of Health, Bethesda, Maryland USA. Available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02003.html. 2 Commission of the European Union. Setting out scientific criteria for the determination of endocrine disrupting properties and amending Annex II to Regulation (EC) 1107/2009. Ref: Ares (2016)3071834e29/06/2016. PART-2016-154327V1.pdf; PART-2016-154328V1.pdf. 3 Scientific principles for the identification of endocrine disrupting chemicals e a consensus statement. The German Federal Institute for Risk Assessment, Berlin, Germany. April 11e12, 2016. http://www.bfr.bund.de/en/international_expert_ meeting_on_endocrine_disruptors-197246.html. 4 WHO/IPCS. 2016. Environmental Health Criteria 240. Principles and Methods for the Risk Assessment of Chemicals in Food. Chapter 4 Hazard Identification and Characterization: Toxicological and Human Studies. http://apps.who.int/iris/ bitstream/10665/44065/7/WHO_EHC_240_7_eng_Chapter4.pdf?ua1⁄41.

Allowing pseudoscience into EU risk assessment processes is eroding public trust in science experts and in science as a whole : The bigger picture

Transparency document related to this article can be found online at http://dx.doi.org/10.1016/j.cbi.2016.07.023.

Upholding science in health, safety and environmental risk assessments and regulations

A public appeal has been advanced by a large group of scientists, concerned that science has been misused in attempting to quantify and regulate unmeasurable hazards and risks.1 The appeal recalls that science is unable to evaluate hazards that cannot be measured, and that science in such cases should not be invoked to justify risk assessments in health, safety and environmental regulations. The appeal also notes that most national and international statutes delineating the discretion of regulators are ambiguous about what rules of evidence ought to apply. Those statutes should be revised to ensure that the evidence for regulatory action is grounded on the standards of the scientific method, whenever feasible. When independent scientific evidence is not possible, policies and regulations should be informed by publicly debated trade-offs between socially desirable uses and social perceptions of affordable precaution. This article explores the premises, implications and actions supporting the appeal and its objectives.

Patterns of Congenital Lower Urinary Tract Obstructive Uropathy

over the fetal membranes occurs more frequently than the complete form. A continuum exists between such cases and complete PM [3]. It has also been hypothesized, albeit without proof, that previous endometritis, traumatic repetition of endometrial curettage, adenomyosis, atrophy, or hypoplasia of the endometrium are important factors in the causation of PM [1]. It is important to recognize PM because of the risks to the pregnancy and the mother. Painless recurrent vaginal bleeding should raise the clinical suspicion of PM. Placenta membranacea may be detected by ultrasound scan but is frequently missed [3]. A low-lying placenta should raise that possibility. However, because of variability of clinical presentation, postpartum inspection of all placentas is important to exclude PM. Placenta membranacea has a characteristic gross appearance, whereas a layer of placental cotyledons of variable thickness is uniformly distributed over the full extent of the membranes [2]. Histologically, the amniotic and chorionic layers of the membranes are absent, which are then replaced by placental villi. Frequently, however, completely formed villi are not seen, but rather a trophoblastic layer invading the membranes.