Integrated testing strategies for cost-sensitive time-efficient hazard classification of new chemicals: The case of skin sensitization.

We offer an alternative approach to toxicological risk assessment of new chemicals. We combine Operations Research techniques with those from Machine Learning to tackle the decision-making process. More specifically, we use Markov decision processes and Bayesian networks to derive the optimal cost-sensitive time-efficient Integrated Testing Strategies for chemical hazard classification under minimal expected cost in a mathematically rigorous fashion.

A new paradigm for regulatory sciences.

Regulatory science, rooted in legal requirements, provides a mechanism for identifying, assessing, and managing harm to humans and the environment from exposure to hazardous substances. A challenge for regulatory authorities is that many governing laws reflect the scientific paradigm of the mid-20th century. By the nature of legislative processes, most laws are not able to readily adapt to incorporate scientific advances that are inherent in an ever-evolving paradigm.

Analysis of health concerns not addressed by REACH for low tonnage chemicals and opportunities for new approach methodology.

In Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) the criterion for deciding the studies that must be performed is the annual tonnage of the chemical manufactured or imported into the EU. The annual tonnage may be considered as a surrogate for levels of human exposure but this does not take into account the physico-chemical properties and use patterns that determine exposure. Chemicals are classified using data from REACH under areas of health concern covering effects on the skin and eye; sensitisation; acute, repeated and prolonged systemic exposure; effects on genetic material; carcinogenicity; and reproduction and development.

Transforming the evaluation of agrochemicals.

The present agrochemical safety evaluation paradigm is long-standing and anchored in well-established testing and evaluation procedures. However, it does not meet the present-day challenges of rapidly growing populations, food insecurity, and pressures from climate change. To transform the current framework and apply modern evaluation strategies that better support sustainable agriculture, the Health and Environmental Sciences Institute (HESI) assembled a technical committee to reframe the safety evaluation of crop-protection products.

Use of New Approach Methodologies (NAMs) in regulatory decisions for chemical safety: Report from an EPAA Deep Dive Workshop.

New Approach Methodologies (NAMs) are considered to include any in vitro, in silico or chemistry-based method, as well as the strategies to implement them, that may provide information that could inform chemical safety assessment. Current chemical legislation in the European Union is limited in its acceptance of the widespread use of NAMs. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a 'Deep Dive Workshop' to explore the use of NAMs in chemical safety assessment, the aim of which was to support regulatory decisions, whilst intending to protect human health.

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.

A framework for chemical safety assessment incorporating new approach methodologies within REACH.

The long-term investment in new approach methodologies (NAMs) within the EU and other parts of the world is beginning to result in an emerging consensus of how to use information from in silico, in vitro and targeted in vivo sources to assess the safety of chemicals. However, this methodology is being adopted very slowly for regulatory purposes. Here, we have developed a framework incorporating in silico, in vitro and in vivo methods designed to meet the requirements of REACH in which both hazard and exposure can be assessed using a tiered approach.

The use of Bayesian methodology in the development and validation of a tiered assessment approach towards prediction of rat acute oral toxicity.

There exists consensus that the traditional means by which safety of chemicals is assessed-namely through reliance upon apical outcomes obtained following in vivo testing-is increasingly unfit for purpose. Whilst efforts in development of suitable alternatives continue, few have achieved levels of robustness required for regulatory acceptance. An array of "new approach methodologies" (NAM) for determining toxic effect, spanning in vitro and in silico spheres, have by now emerged.

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.

The modification of cancer risk by chemicals.

Advances in understanding of the process of carcinogenesis have undermined the concept of chemicals being classifiable as either carcinogens or non-carcinogens. Elements of carcinogenesis are happening all the time and a proportion of cancers cannot be prevented, the 'bad luck hypothesis'. Although the proportion that can be prevented is disputed, it is important to continue efforts to reduce it.

Chemical carcinogenicity revisited 2: Current knowledge of carcinogenesis shows that categorization as a carcinogen or non-carcinogen is not scientifically credible.

Developments in the understanding of the etiology of cancer have undermined the 1970s concept that chemicals are either "carcinogens" or "non-carcinogens". The capacity to induce cancer should not be classified in an inflexible binary manner as present (carcinogen) or absent (non-carcinogen). Chemicals may induce cancer by three categories of mode of action: direct interaction with DNA or DNA replication including DNA repair and epigenetics; receptor-mediated induction of cell division; and non-specific induction of cell division.

Chemical carcinogenicity revisited 3: Risk assessment of carcinogenic potential based on the current state of knowledge of carcinogenesis in humans.

Over 50 years, we have learned a great deal about the biology that underpins cancer but our approach to testing chemicals for carcinogenic potential has not kept up. Only a small number of chemicals has been tested in animal-intensive, time consuming, and expensive long-term bioassays in rodents. We now recommend a transition from the bioassay to a decision-tree matrix that can be applied to a broader range of chemicals, with better predictivity, based on the premise that cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from sustained cell proliferation.

Steps towards the international regulatory acceptance of non-animal methodology in safety assessment.

The current animal-based paradigm for safety assessment must change. In September 2016, the UK National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs) brought together scientists from regulatory authorities, academia and industry to review progress in bringing new methodology into regulatory use, and to identify ways to expedite progress. Progress has been slow.

Integrated testing strategies can be optimal for chemical risk classification.

There is an urgent need to refine strategies for testing the safety of chemical compounds. This need arises both from the financial and ethical costs of animal tests, but also from the opportunities presented by new in-vitro and in-silico alternatives. Here we explore the mathematical theory underpinning the formulation of optimal testing strategies in toxicology.

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.

Use of the RISK21 roadmap and matrix: human health risk assessment of the use of a pyrethroid in bed netting.

The HESI-coordinated RISK21 roadmap and matrix are tools that provide a transparent method to compare exposure and toxicity information and assess whether additional refinement is required to obtain the necessary precision level for a decision regarding safety. A case study of the use of a pyrethroid, "pseudomethrin," in bed netting to control malaria is presented to demonstrate the application of the roadmap and matrix. The evaluation began with a problem formulation step.

Risk assessment in the 21st century: roadmap and matrix.

Abstract The RISK21 integrated evaluation strategy is a problem formulation-based exposure-driven risk assessment roadmap that takes advantage of existing information to graphically represent the intersection of exposure and toxicity data on a highly visual matrix. This paper describes in detail the process for using the roadmap and matrix. The purpose of this methodology is to optimize the use of prior information and testing resources (animals, time, facilities, and personnel) to efficiently and transparently reach a risk and/or safety determination.

A 21st century roadmap for human health risk assessment.

The Health and Environmental Sciences Institute (HESI)-coordinated Risk Assessment in the 21st Century (RISK21) project was initiated to develop a scientific, transparent, and efficient approach to the evolving world of human health risk assessment, and involved over 120 participants from 12 countries, 15 government institutions, 20 universities, 2 non-governmental organizations, and 12 corporations. This paper provides a brief overview of the tiered RISK21 framework called the roadmap and risk visualization matrix, and articulates the core principles derived by RISK21 participants that guided its development. Subsequent papers describe the roadmap and matrix in greater detail.

Using mode of action information to improve regulatory decision-making: an ECETOC/ILSI RF/HESI workshop overview.

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), the International Life Sciences Institute (ILSI) Research Foundation (RF), and the ILSI Health and Environmental Sciences Institute (HESI) hosted a workshop in November 2009 to review current practice in the application of mode of action (MOA) considerations in chemical risk assessment. The aim was to provide a rationale for a more general, but flexible approach and to propose steps to facilitate broader uptake and use of the MOA concept. There was consensus amongst the workshop participants that it will require substantial effort and cooperation from the multiple disciplines involved to embrace a common, consistent, and transparent approach.

Strengthening the reliability and credibility of observational epidemiology studies by creating an Observational Studies Register.

Objective: To evaluate the need for the creation of a system in which observational epidemiology studies are registered; an Observational Studies Register (OSR).

Study Design And Setting: The current scientific process for observational epidemiology studies is described. Next, a parallel is made with the clinical trials area, where the creation of clinical trial registers has greatly restored and improved their credibility and reliability.