Systems Biology and Biomarkers of Early Effects for Occupational Exposure Limit Setting

Figures & data

Figure 1 Continuum from exposure to disease. Adapted from NRC⁽⁹⁾ and Schulte and Perera.⁽¹⁰⁾. Reproduced from Environmental Health Perspectives.

Table 1 Glossary of Key Terms

Key Term	Definition
Benchmark dose	A dose of a substance that when absorbed produces a predetermined change in the response rate of an adverse effect relative to the background response rate of this effect.
Benchmark response (BMR)	A predetermined change in the response rate of an adverse effect relative to the background response rate of this effect. The BMR is the basis for deriving benchmark doses.^(^50^)
Biological-based dose response models (BBDR)	A predictive model that describes biological processes at the cellular and molecular level linking the target organ dose to the adverse effect.^(^96^)
Biomarkers	Internal measures or markers of exposures or effects for a chemical or agent in the body.
Biomarkers of exposure	The chemical or its metabolite or the product of an interaction between a chemical and some target molecule or cell that is measured in a compartment in an organism.^(^97^)
Biomarker of effect	A measurable biochemical, physiologic, behavioral, or other alteration in an organism that, depending on the magnitude, can be recognized as associated with an established or possible health impairment or disease.^(^97^)
Biomarker of susceptibility	An indicator of an inherent or acquired ability of an organism to respond to the challenge of exposure to a specific chemical substance.^(^97^)
Computational Toxicology	Computational toxicology identifies trends and patterns in biomarker and chemistry datasets.^(^19^)
Genomics	Refers to the entire genome of an organism whereas genetics is the study of a specific gene.
Exposome	Concept by Wild^(^37^) defined as the totality of exposure over a life time beginning in utero until death and the impact those exposures have on health.
High throughput screening (HTS)	Experiments that can be automated and rapidly performed to measure the effect of substances on a biologic process of interest. These assays can evaluate hundreds to many thousands of chemicals over a wide concentration range to identify chemical actions on gene, pathway, and cell function.
Lowest observed adverse effect level (LOAEL)	The lowest exposure level at which there are biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control group.^(^96^)
Metabolomics	Studies the metabolic products of the human body and provides a comprehensive view of cellular metabolic changes in small molecules and byproducts.^(^98^) The metabolomics-driven approaches may provide insight into complex biochemical processes and the MOA and toxicity of chemicals.^(^99^,^100^)
No observed adverse effect level (NOAEL)	The highest exposure level at which there are no biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control; some effects may be produced at this dose level, but they are not considered adverse or precursors of adverse effects.^(^96^)
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Table NaN Glossary of Key Terms (Continued)

Key Term	Definition
-omics technology	The collective characterization of components and measurement of molecules from a biological field of study, which involves large scale data acquisition system that can be used to measure biological states or responses; examples include genomics, proteomics, transcriptomics, and toxicogenomics.
Proteomics	Involves the identification, characterization, and quantitation of expressed proteins in biological samples. Provides complementary functional information to genomics.
Systems biology	An approach used to integrate biological data to understand how biological systems function.
Toxicogenomics	Brings together toxicology, genetics, and molecular biology such as transcriptomics, proteomics, and environmental health to understand the response of an organism to an external insult. The promise of this technology is that biomarkers of exposure and effect can be elucidated.^(^7^) Insight into the mechanism of action and low-dose effects are other benefits.
Transcriptomics	The study of RNA transcripts that result in gene expression.
Uncertainty factors	A numerical value (often a factor of 3 or 10) used to adjust a point of departure (e.g., generally a no observed/lowest observed adverse effect level or benchmark dose) in order to derive a reference concentration or reference dose. Uncertainty factors are applied as needed to account for extrapolation of results in experimental animals to humans, inter-individual variability including sensitive subgroups, extrapolation from a NOAEL or LOAEL, extrapolation of results from subchronic exposures to chronic exposures, and database inadequacies.^(^101^)

Table 2 Definitions of Acronyms

ANOVA	Analysis of variance
BMD	Benchmark dose
BMDL	Benchmark dose and associated lower confidence limit
BBDR	Biologically-Based Dose Response
EPA	Environmental Protection Agency
FDA	Food and Drug Administration
FEL	Frank effect level
HTS	High throughput screening
LOAEL	Lowest observed adverse effect levels
MOA	Mode of action
NAS	National Academy of Sciences
NIH	National Institutes of Health
NIOSH	National Institute for Occupational Safety and Health
NOAEL	No observed adverse effect level
NOEL	No observed effect level
NRC	National Research Council
OEL	Occupational exposure limit
PBPK	Physiological-based pharmacokinetic
REACH	Registration, Evaluation, Authorisation, and Restriction of Chemicals

Table 3 Efforts Affecting the Use of 21^st Century Technologies and Risk Assessment

Group	Name	Result/Goals
European Commission	Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH)^(^14^)	Determination of risk of chemicals to improve the protection of human health and the environment
National Research Council	Toxicity Testing in the 21^st Century^(^3^)	Recommendations for greater use of in vitro testing and computational approaches
National Research Council	Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment^(^1^)	Recommendations for use of toxicogenomic technologies in risk assessment
National Academy of Sciences	Meeting on Use of Emerging Science for Environmental Health Decisions^(^19^)	Discussion of promise of computational toxicology for policy decisions
National Research Council	Science and Decisions: Advancing Risk Assessment^(^28^)	Recommendations for improvements in the science and practice of risk assessment
EPA	NexGen^(^101^)	Evaluation of use of HTS, computational toxicology and systems modeling for risk assessment

Figure 2 Biologic responses as a result of an exposure. The intersection results in perturbation of biologic pathways. When perturbations are sufficiently large or when the host is unable to adapt because of underlying nutritional, genetic, disease, or life-stage status, biologic function is compromised, and this leads to toxicity and disease.⁽⁹⁴⁾ © Elsevier. Reproduced by permission of Elsvier. Permission to reuse must be obtained from the rightsholder.

Table 4 Different Types of Biomarkers

Type of Biomarker	Characteristics	Example
Exposure	Measurement that reflects biologically effective and internal dose	Urine or blood concentration of agent
Effect	Measurable biochemical, physiological, or other alteration that can be recognized as a potential health impairment^(^102^)	DNA mutation or cytogenetic change
Susceptibility	Inherent or acquired sensitivities or resistance in response to specific exposures	Genetic polymorphisms in metabolic activation/deactivation enzymes

Table 5 Examples of -Omics Technologies

Technology	Parameters
Proteomics	Involves the identification, characterization and quantitation of expressed proteins in biological samples. Provides complementary functional information to genomics.
Metabolomics	Studies the metabolic products of the human body and provides a comprehensive view of cellular metabolic changes in small molecules and by-products.^(^98^) The metabolomics-driven approaches may provide insight into complex biochemical processes and the MOA and toxicity of chemicals.^(^99^,^100^)
Toxicogenomics	Brings together toxicology, genetics, and molecular biology such as transcriptomics, proteomics, and environmental health to understand the response of an organism to an external insult. The promise of this technology is that biomarkers of exposure and effect can be elucidated.^(^7^) Insight into the mechanism of action and low-dose effects are other benefits.

Table 6 Uses of Biomarkers in Hazard Characterization and Dose-Response Analysis

Aids in the identification of mode of action in support of risk assessment

Extends the dose-response curve to lower levels of exposure

Addresses uncertainty and variability including interspecies differences and identifying susceptible population

Figure 3 Frequency distribution of a biomarker (physiological parameter) in two hypothetical populations to illustrate the effect of exposure and susceptibility factors. Adapted from Woodruff et al.⁽⁹⁵⁾. Reproduced from Environmental Health Perspectives.

Table 7 Effect Levels, by Severity, That are Considered in the Derivation of Exposure Limits

Effect or No Effect Level	General Effect
NOEL	No observed biological effects in the exposed population
NOAEL	Effects may be seen at this level but not considered to be adverse
	a) Enzyme induction or other biochemical change, consistent with possible mechanism of action, with no pathological changes and no change in organ weights
	b) Enzyme induction and subcellular proliferation or other changes in organelles, consistent with possible mechanism of action, but not other apparent effects.
	c) Hyperplasia, hypertrophy, or atrophy, but no changes in organ weights
LOAEL	Lowest exposure concentration where adverse effects are seen between the exposed and the control population.
	a) Reversible cellular changes including cloudy swelling, hydropic change or fatty changes
	b) Degenerative or necrotic tissues with no apparent decrement in organ function
FEL	Exposure level in which unmistakable adverse effects are seen that are likely to be irreversible
	a) Pathological changes with definite organ dysfunctions
	b) Pronounced pathological changes with severe organ dysfunction with long-term sequelae

Notes: NOEL – No Observed Effect Level; NOAEL – No Observed Adverse Effect Level; LOAEL – Lowest Observed Adverse Effect Level; FEL – Frank Effect Level. Adapted from EPA.⁽¹⁰³⁾

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