9.1 Hazard identification

Hazard identification is the crucial first step in assessing chemical risks. It involves systematically reviewing scientific data to determine if a substance can harm humans or the environment. This process lays the foundation for subsequent risk assessment steps.

The process includes literature reviews, evaluating study quality, and analyzing evidence from various sources. It considers different types of toxicity, from acute to chronic effects, and examines data from human, animal, and laboratory studies to build a comprehensive understanding of potential hazards.

Definition of hazard identification

• Hazard identification is the first step in the risk assessment process that involves identifying the potential adverse health effects that may be caused by exposure to a substance or agent
• Focuses on determining whether a substance has the potential to cause harm to humans or the environment based on available scientific evidence
• Involves a systematic review and evaluation of the available toxicological and epidemiological data to identify the types of health effects that may be associated with exposure to a substance

Role in risk assessment process

• Hazard identification provides the foundation for the subsequent steps in the risk assessment process, including dose-response assessment, exposure assessment, and risk characterization
• The information gathered during hazard identification is used to determine the critical effects and the doses at which those effects occur, which are then used to establish safe exposure levels

Relationship to dose-response assessment

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• Dose-response assessment builds upon the hazard identification step by quantifying the relationship between the dose or exposure level of a substance and the incidence or severity of the adverse health effects
• The data from hazard identification, such as the types of effects observed and the doses at which they occur, are used to develop dose-response models and identify the critical effect and the point of departure for risk assessment

Relationship to exposure assessment

• Exposure assessment estimates the magnitude, frequency, and duration of human exposure to a substance, taking into account various exposure pathways and routes
• The information from hazard identification, such as the target organs and the relevant exposure routes, guides the exposure assessment process and helps determine the most appropriate exposure scenarios to evaluate

Relationship to risk characterization

• Risk characterization integrates the information from hazard identification, dose-response assessment, and exposure assessment to estimate the likelihood and magnitude of adverse health effects in a population
• The hazard identification step provides the qualitative description of the potential health effects, while the dose-response and exposure assessments provide the quantitative data needed to characterize the risk

Key steps in hazard identification

• Hazard identification involves a systematic and comprehensive evaluation of the available scientific evidence to identify the potential adverse health effects of a substance
• The process typically includes several key steps, such as literature review and data gathering, evaluation of study quality and reliability, and weight of evidence analysis

Literature review and data gathering

• Comprehensive search and review of the scientific literature, including published studies, government reports, and other relevant sources of information
• Gathering of data on the physical and chemical properties of the substance, its uses and exposure patterns, and any available toxicological and epidemiological studies
• Identification of data gaps and limitations that may need to be addressed through additional research or testing

Evaluation of study quality and reliability

• Assessment of the quality, reliability, and relevance of the available studies based on factors such as study design, sample size, dose levels, route of exposure, and statistical analysis
• Consideration of potential sources of bias, confounding factors, and limitations that may affect the interpretation of the results
• Evaluation of the consistency and reproducibility of the findings across different studies and endpoints

Weight of evidence analysis

• Integration and synthesis of the available evidence from multiple lines of inquiry, including human, animal, and mechanistic studies
• Assessment of the strength, consistency, and coherence of the evidence for each endpoint or effect of concern
• Consideration of the biological plausibility and relevance of the observed effects to human health, taking into account factors such as mode of action, species differences, and potential confounding factors

Types of data used

• Hazard identification relies on a variety of data sources and types of studies to assess the potential adverse health effects of a substance
• The most commonly used types of data include human epidemiological studies, animal toxicology studies, in vitro and mechanistic studies, and structure-activity relationships

Human epidemiological studies

• Observational studies that examine the relationship between exposure to a substance and the occurrence of health effects in human populations (cohort studies, case-control studies)
• Provide direct evidence of the effects of a substance on human health under real-world exposure conditions
• Can be limited by factors such as confounding, bias, and exposure misclassification, and may not be available for all substances or endpoints of concern

Animal toxicology studies

• Experimental studies that assess the toxicity of a substance in laboratory animals (rodents, dogs, monkeys) under controlled conditions
• Allow for the evaluation of a wide range of endpoints and dose levels, and can provide information on the mechanisms and modes of action of a substance
• May be limited by species differences and the need to extrapolate the results to humans, and may not always predict the effects of chronic, low-dose exposures

In vitro and mechanistic studies

• Laboratory studies that examine the effects of a substance on isolated cells, tissues, or biochemical processes
• Provide insights into the molecular and cellular mechanisms of toxicity and can help identify potential targets and pathways of toxicity
• Can be used to screen large numbers of substances and prioritize them for further testing, but may not always reflect the complexity of whole-organism responses

Structure-activity relationships

• Computational methods that predict the toxicity of a substance based on its chemical structure and properties, and the known effects of similar substances
• Can be used to fill data gaps and prioritize substances for further testing, but may have limited predictive power for novel or complex substances
• Require validation and refinement based on experimental data and expert judgment

Endpoints and effects considered

• Hazard identification considers a wide range of adverse health effects and endpoints that may be associated with exposure to a substance
• The specific endpoints and effects considered depend on the nature of the substance, the available data, and the regulatory context, but typically include acute and chronic toxicity, local and systemic effects, and specific types of toxicity such as carcinogenicity, reproductive toxicity, and neurotoxicity

Acute vs chronic toxicity

• Acute toxicity refers to the adverse effects that occur after a single or short-term exposure to a substance, typically at high doses (poisoning, irritation, sensitization)
• Chronic toxicity refers to the adverse effects that occur after repeated or long-term exposure to a substance, typically at lower doses (cancer, organ damage, developmental effects)
• The dose-response relationship and the underlying mechanisms may differ between acute and chronic toxicity, and both types of effects need to be considered in hazard identification

Local vs systemic effects

• Local effects refer to the adverse effects that occur at the site of contact or entry of a substance into the body (skin irritation, respiratory tract irritation)
• Systemic effects refer to the adverse effects that occur in organs or tissues distant from the site of exposure, after the substance has been absorbed and distributed in the body (liver toxicity, kidney damage)
• The route of exposure and the pharmacokinetic properties of the substance determine whether the effects are primarily local or systemic

Reversible vs irreversible effects

• Reversible effects are those that can be mitigated or reversed after exposure to the substance has ceased, either spontaneously or with medical intervention (mild irritation, temporary enzyme inhibition)
• Irreversible effects are those that persist or progress even after exposure has ceased, and may result in permanent damage or dysfunction (cancer, birth defects, organ failure)
• The severity and reversibility of the effects are important considerations in hazard identification and risk assessment, as they influence the level of concern and the regulatory actions that may be needed

Carcinogenicity and mutagenicity

• Carcinogenicity refers to the ability of a substance to cause cancer, either by inducing mutations in DNA (genotoxic carcinogens) or by promoting the growth and proliferation of cancer cells (non-genotoxic carcinogens)
• Mutagenicity refers to the ability of a substance to cause mutations in DNA, which may lead to cancer or other adverse effects (birth defects, heritable genetic disorders)
• The evaluation of carcinogenicity and mutagenicity typically involves a combination of epidemiological studies, animal bioassays, and in vitro genotoxicity tests, and may require specialized study designs and data analysis methods

Reproductive and developmental toxicity

• Reproductive toxicity refers to the adverse effects of a substance on sexual function, fertility, and the development of offspring, which may occur in either males or females (reduced sperm count, impaired ovulation, early pregnancy loss)
• Developmental toxicity refers to the adverse effects of a substance on the developing embryo or fetus, which may result in birth defects, growth retardation, or functional impairments (neural tube defects, intellectual disability)
• The evaluation of reproductive and developmental toxicity typically involves a combination of epidemiological studies, animal reproductive toxicity studies, and specialized tests such as the two-generation reproductive toxicity study and the developmental neurotoxicity study

Neurotoxicity and behavioral effects

• Neurotoxicity refers to the adverse effects of a substance on the structure or function of the nervous system, which may result in neurological or behavioral impairments (memory loss, motor dysfunction, sensory disturbances)
• Behavioral effects refer to the changes in behavior or cognitive function that may result from exposure to a substance, either as a direct effect on the nervous system or as a secondary consequence of other toxicities (anxiety, aggression, learning deficits)
• The evaluation of neurotoxicity and behavioral effects may involve a combination of epidemiological studies, animal neurotoxicity studies, and specialized tests such as the functional observational battery and the motor activity test

Immunotoxicity and sensitization

• Immunotoxicity refers to the adverse effects of a substance on the immune system, which may result in increased susceptibility to infections, autoimmune diseases, or cancer (immunosuppression, autoimmunity)
• Sensitization refers to the induction of an allergic response to a substance upon repeated exposure, which may manifest as skin reactions, respiratory symptoms, or anaphylaxis (contact dermatitis, asthma)
• The evaluation of immunotoxicity and sensitization may involve a combination of epidemiological studies, animal immunotoxicity studies, and specialized tests such as the local lymph node assay and the mouse ear swelling test

Challenges and limitations

• Hazard identification is a complex and iterative process that involves the integration of data from multiple sources and the consideration of various uncertainties and limitations
• Some of the key challenges and limitations in hazard identification include data gaps and uncertainties, species differences and extrapolation, mixture effects and interactions, and low-dose extrapolation and non-monotonic dose-response relationships

Data gaps and uncertainties

• Lack of data on the toxicity of some substances, particularly for newer or less studied chemicals, which may require the use of alternative methods such as read-across or quantitative structure-activity relationships (QSARs)
• Variability and uncertainty in the available data, due to differences in study design, exposure conditions, or population characteristics, which may affect the reliability and relevance of the results
• Need for expert judgment and weight of evidence approaches to integrate and interpret the available data, taking into account the strengths and limitations of each study and the overall coherence of the evidence

Species differences and extrapolation

• Differences in the pharmacokinetics, metabolism, and sensitivity of different species to the toxic effects of a substance, which may limit the relevance of animal data for predicting human health risks
• Need for interspecies extrapolation factors or physiologically based pharmacokinetic (PBPK) modeling to account for species differences in toxicity and to estimate equivalent doses for humans
• Potential for species-specific effects or modes of action that may not be relevant or predictive for humans, which may require additional data or mechanistic understanding to resolve

Mixture effects and interactions

• Exposure to multiple substances or stressors in real-world scenarios, which may result in additive, synergistic, or antagonistic effects that are not captured by single-substance toxicity testing
• Need for methods to assess the joint toxicity of mixtures, such as component-based approaches, whole mixture testing, or statistical modeling, depending on the nature and complexity of the mixture
• Potential for pharmacokinetic or pharmacodynamic interactions among mixture components, which may alter the absorption, distribution, metabolism, or excretion of the substances or their toxic effects

Low-dose extrapolation and non-monotonic dose-response

• Challenges in extrapolating the effects observed at high doses in animal studies to the low doses that are relevant for human exposures, particularly for substances with non-linear or threshold dose-response relationships
• Potential for non-monotonic dose-response relationships, where the effects of a substance may increase or decrease at different dose levels, which may complicate the derivation of safe exposure levels or reference doses
• Need for specialized study designs and statistical methods to characterize low-dose effects and non-monotonic dose-response relationships, such as the benchmark dose approach or the use of multiple dose groups and spacing factors

Regulatory applications and implications

• Hazard identification is a critical step in the regulatory assessment and management of chemical risks, and has important implications for public health and environmental protection
• The information from hazard identification is used to inform various regulatory decisions and actions, such as hazard classification and labeling, priority setting for further testing, and risk management and decision-making

Hazard classification and labeling

• Classification of substances into different hazard categories based on their intrinsic toxicological properties and the severity of the effects, using standardized criteria and cut-off values (Globally Harmonized System of Classification and Labelling of Chemicals, GHS)
• Labeling of substances with appropriate hazard pictograms, signal words, and hazard and precautionary statements, to communicate the potential risks and safe handling practices to workers and consumers
• Use of hazard classification and labeling information in the development of safety data sheets (SDS), transport regulations, and other risk communication tools

Priority setting for further testing

• Identification of substances that require further testing or evaluation based on the available hazard information, the potential for human exposure, and the regulatory context
• Use of screening and prioritization methods, such as the Toxicity Forecaster (ToxCast) and the Endocrine Disruptor Screening Program (EDSP), to identify substances of potential concern and guide the allocation of testing resources
• Development of integrated testing strategies and tiered approaches that combine different types of data and testing methods, such as in silico, in vitro, and in vivo assays, to optimize the efficiency and effectiveness of hazard assessment

Risk management and decision-making

• Use of hazard identification information, along with exposure and risk assessment data, to support risk management decisions and regulatory actions, such as setting exposure limits, restricting certain uses or applications, or requiring additional risk mitigation measures
• Consideration of the societal, economic, and technological factors that may influence the acceptability and feasibility of different risk management options, and the need for stakeholder engagement and risk-benefit analysis
• Integration of hazard identification into broader risk assessment and management frameworks, such as the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation in the European Union or the Toxic Substances Control Act (TSCA) in the United States, to ensure a comprehensive and science-based approach to chemical safety