Treatment and removal strategies for estrogens from wastewater

Natural and synthetic steroidal estrogens (estrone, 17β-estradiol and 17α-ethinylestradiol) are endocrine disrupters, that are discharged consistently from the sewage treatment works into surface waters, thereby causing endocrine disrupting effects to aquatic organisms at trace concentrations (nanogram per litre). Several years of research have been focused on their fate, behaviour and removal in the environment but primarily in the sewage treatment works which acts as a sink for these compounds. This review attempts to summarize the factors involved in the removal of these chemicals from the sewage treatment works. Biological processes, and to a limited extent physio-chemical properties, play a vital role in the endocrinal deactivation of which these compounds. The efficiency of these processes is highly dependent on operating parameters (such as sludge retention time, redox potential, etc) that govern the secondary treatment process of a functional sewage treatment works. Although advanced treatment technologies are available, cost and operational considerations do not make them a sustainable solution

Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective

After over 60 years of therapeutic use in the UK, paracetamol (acetaminophen, N-acetyl-p-aminophenol, APAP) remains the subject of considerable research into both its mode of action and toxicity. The pharmacological properties of APAP are the focus of some activity, with the role of the metabolite N-arachidonoylaminophenol (AM404) still a topic of debate. However, that the hepatotoxicity of APAP results from the production of the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI/NABQI) that can deplete glutathione, react with cellular macromolecules, and initiate cell death, is now beyond dispute. The disruption of cellular pathways that results from the production of NAPQI provides a source of potential biomarkers of the severity of the damage. Research in this area has provided new diagnostic markers such as the microRNA miR-122 as well as mechanistic biomarkers associated with apoptosis, mitochondrial dysfunction, inflammation and tissue regeneration. Additionally, biomarkers of, and systems biology models for, glutathione depletion have been developed. Furthermore, there have been significant advances in determining the role of both the innate immune system and genetic factors that might predispose individuals to APAP-mediated toxicity. This perspective highlights some of the progress in current APAP-related research

Workshop report on the evaluation of the updated and expanded carcinogen database to support derivation of threshold of toxicological concern values for DNA reactive carcinogens

Threshold of toxicological concern (TTC) values are frequently used for compounds occurring at low concentrations in feed and food or as impurities in drugs. This workshop report addresses the emerging alternatives for deriving TTC values for DNA reactive carcinogens and evaluating the acceptability of the Cramer Class TTC values to be adequately protective for non-DNA reactive carcinogens

Classification schemes for carcinogenicity based on hazard - identification have become outmoded and serve neither science nor society

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

The codification of hazard and its impact on the hazard versus risk controversy

The long running controversy about the relative merits of hazard-based versus risk-based approaches has been investigated. There are three levels of hazard codification: level 1 divides chemicals into dichotomous bands of hazardous and non-hazardous; level 2 divides chemicals into bands of hazard based on severity and/or potency; and level 3 places each chemical on a continuum of hazard based on severity and/or potency. Any system which imposes compartments onto a continuum will give rise to issues at the boundaries, especially with only two compartments. Level 1 schemes are only justifiable if there is no variation in severity, or potency or if there is no threshold. This is the assumption implicit in GHS/EU classification for carcinogenicity, reproductive toxicity and mutagenicity. However, this assumption has been challenged. Codification level 2 hazard assessments offer a range of choices and reduce the built-in conflict inherent in the level 1 process. Level 3 assessments allow a full range of choices between the extremes and reduce the built-in conflict even more. The underlying reason for the controversy between hazard and risk is the use of level 1 hazard codification schemes in situations where there are ranges of severity and potency which require the use of level 2 or level 3 hazard codification. There is not a major difference between level 2 and level 3 codification, and they can both be used to select appropriate risk management options. Existing level 1 codification schemes should be reviewed and developed into level 2 schemes where appropriate

A new approach to the classification of carcinogenicity.

Concern over substances that may cause cancer has led to various classification schemes to recognize carcinogenic threats and provide a basis to manage those threats. The least useful schemes have a binary choice that declares a substance carcinogenic or not. This overly simplistic approach ignores the complexity of cancer causation by considering neither how the substance causes cancer, nor the potency of that mode of action. Consequently, substances are classified simply as "carcinogenic", compromising the opportunity to properly manage these kinds of substances. It will likely be very difficult, if not impossible, to incorporate New Approach Methodologies (NAMs) into binary schemes. In this paper we propose a new approach cancer classification scheme that segregates substances by both mode of action and potency into three categories and, as a consequence, provides useful guidance in the regulation and management of substances with carcinogenic potential. Examples are given, including aflatoxin (category A), trichlorethylene (category B), and titanium dioxide (category C), which demonstrate the clear differentiation among these substances that generate appropriate levels of concern and management options

New ideas for non-animal approaches to predict repeated-dose systemic toxicity: Report from an EPAA Blue Sky Workshop

© 2020 The Authors The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a ‘Blue Sky Workshop’ on new ideas for non-animal approaches to predict repeated-dose systemic toxicity. The aim of the Workshop was to formulate strategic ideas to improve and increase the applicability, implementation and acceptance of modern non-animal methods to determine systemic toxicity. The Workshop concluded that good progress is being made to assess repeated dose toxicity without animals taking advantage of existing knowledge in toxicology, thresholds of toxicological concern, adverse outcome pathways and read-across workflows. These approaches can be supported by New Approach Methodologies (NAMs) utilising modern molecular technologies and computational methods. Recommendations from the Workshop were based around the needs for better chemical safety assessment: how to strengthen the evidence base for decision making; to develop, standardise and harmonise NAMs for human toxicity; and the improvement in the applicability and acceptance of novel techniques. “Disruptive thinking” is required to reconsider chemical legislation, validation of NAMs and the opportunities to move away from reliance on animal tests. Case study practices and data sharing, ensuring reproducibility of NAMs, were viewed as crucial to the improvement of non-animal test approaches for systemic toxicity.U.S.Environmental Protection Agency (EPA); Agency for Science, Technology and Research ( A*STAR), Singapor

Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis

BACKGROUND: Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. OBJECTIVES: We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-–mediated mode of action was specifically explored. RESULTS: We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. CONCLUSIONS: The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population

Identifying an indoor air exposure limit for formaldehyde considering both irritation and cancer hazards

Formaldehyde is a well-studied chemical and effects from inhalation exposures have been extensively characterized in numerous controlled studies with human volunteers, including asthmatics and other sensitive individuals, which provide a rich database on exposure concentrations that can reliably produce the symptoms of sensory irritation. Although individuals can differ in their sensitivity to odor and eye irritation, the majority of authoritative reviews of the formaldehyde literature have concluded that an air concentration of 0.3 ppm will provide protection from eye irritation for virtually everyone. A weight of evidence-based formaldehyde exposure limit of 0.1 ppm (100 ppb) is recommended as an indoor air level for all individuals for odor detection and sensory irritation. It has recently been suggested by the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and the US Environmental Protection Agency (US EPA) that formaldehyde is causally associated with nasopharyngeal cancer (NPC) and leukemia. This has led US EPA to conclude that irritation is not the most sensitive toxic endpoint and that carcinogenicity should dictate how to establish exposure limits for formaldehyde. In this review, a number of lines of reasoning and substantial scientific evidence are described and discussed, which leads to a conclusion that neither point of contact nor systemic effects of any type, including NPC or leukemia, are causally associated with exposure to formaldehyde. This conclusion supports the view that the equivocal epidemiology studies that suggest otherwise are almost certainly flawed by identified or yet to be unidentified confounding variables. Thus, this assessment concludes that a formaldehyde indoor air limit of 0.1 ppm should protect even particularly susceptible individuals from both irritation effects and any potential cancer hazard