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No-observed-adverse-effect level
No-observed-adverse-effect level
No-observed-adverse-effect level
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The no-observed-adverse-effect level (NOAEL) denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effects of the tested protocol. In drug development, the NOAEL of a new drug is assessed in laboratory animals, such as mice, prior to initiation of human trials in order to establish a safe clinical starting dose in humans. The OECD publishes guidelines for Preclinical Safety Assessments, in order to help scientists discover the NOAEL.[1]

Synopsis

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Some adverse effects in the exposed population when compared to its appropriate control might include alteration of morphology, functional capacity, growth, development or life span. The NOAEL is determined or proposed by qualified personnel, often a pharmacologist or a toxicologist.[citation needed]

The NOAEL could be defined as "the highest experimental point that is without adverse effect," meaning that under laboratory conditions, it is the level where there are no side effects. It either does not provide the effects of drug with respect to duration and dose, or it does not address the interpretation of risk based on toxicologically relevant effects.[2]

In toxicology it is specifically the highest tested dose or concentration of a substance (i.e. a drug or chemical) or agent (e.g. radiation), at which no such adverse effect is found in exposed test organisms where higher doses or concentrations resulted in an adverse effect.[3][4][5]

The NOAEL level may be used in the process of establishing a dose–response relationship,[6] a fundamental step in most risk assessment methodologies.[5]

Synonyms

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The NOAEL is also known as NOEL (no-observed-effect level) as well as NEC (no-effect concentration) and NOEC (no-observed-effect concentration).[7][8]

US EPA definition

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The United States Environmental Protection Agency defines NOAEL as 'an exposure level at which there are no statistically or 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 level, but they are not considered as adverse, or as precursors to adverse effects.[5] In an experiment with several NOAELs, the regulatory focus is primarily on the highest one, leading to the common usage of the term NOAEL as the highest exposure without adverse effects.'[9]

See also

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References

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No-observed-adverse-effect level

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from Grokipedia
The no-observed-adverse-effect level (NOAEL) is defined as the highest dose or exposure level of a chemical, , or other substance at which no statistically or biologically significant adverse effects are observed in the exposed population compared to an unexposed control group, under specified conditions of exposure. This threshold represents a critical point in dose-response relationships, distinguishing safe exposure from levels that may cause harm, such as alterations in morphology, function, growth, development, or lifespan of target organisms. In and , the NOAEL serves as a foundational datum for deriving health guidance values, including the U.S. Environmental Protection Agency's reference dose (RfD), the and Drug Administration's (ADI) for food additives, and the Agency for Toxic Substances and Disease Registry's minimal risk level (MRL). In pharmaceutical , NOAEL informs the establishment of safe starting doses and margins of safety. These values are typically calculated by dividing the NOAEL by uncertainty factors (often 10 to 1000) to account for interspecies differences, intraspecies variability, exposure duration, and , ensuring a margin of for sensitive populations. The NOAEL is identified from controlled studies, such as subchronic or tests in animals, where multiple dose levels are administered, and effects are evaluated against endpoints like organ function, , and reproductive outcomes. Distinguished from the broader no-observed-effect level (NOEL), which may encompass non-adverse changes, the NOAEL specifically excludes any deleterious outcomes, focusing on toxicological relevance. While traditionally determined as the highest non-toxic dose in categorical study designs, contemporary risk assessments increasingly supplement or replace it with the benchmark dose (BMD) approach, which models continuous dose-response data for greater precision and reduced uncertainty. This evolution addresses limitations of the NOAEL, such as its dependence on dose spacing and sample size, which can lead to variability in estimates.

Definition and Core Concepts

Primary Definition

The no-observed-adverse-effect level (NOAEL) is defined as the highest exposure level (dose or concentration) of a substance at which there is no statistically or biologically significant increase in the frequency or severity of adverse effects observed in an exposed population compared to an appropriate control group. This threshold is determined through dose-response studies, where exposures are systematically varied to identify the point below which no harmful outcomes occur. An "" in this refers to any undesirable and potentially pathologic change in body structure or function, including alterations in morphology, functional capacity, growth, development, or life span of target organisms, as detectable by clinical, physiological, biochemical, histological, or other relevant tests. Importantly, adaptive responses that do not impair normal physiological function, such as induction without , are not considered adverse and thus do not preclude a level from being classified as a NOAEL. NOAEL is primarily established in non-clinical studies, such as animal toxicity tests (e.g., repeated-dose oral or studies in ), to derive safe exposure thresholds for humans by applying uncertainty factors to account for interspecies and intraspecies variability. For instance, in a 90-day study with doses of 0, 10, 50, and 100 mg/kg/day, if s like organ weight changes or histopathological lesions begin at 50 mg/kg/day, the NOAEL would be 10 mg/kg/day. The term is closely related to the lowest observed level (LOAEL), which represents the lowest dose at which s are detectable, typically immediately above the NOAEL.

Key Distinctions from Similar Terms

The no-observed-adverse-effect level (NOAEL) is distinguished from the no-observed-effect level (NOEL) primarily by its focus on adverse effects alone. While the NOEL represents the highest exposure level at which no effects—adverse or otherwise—are observed, including any detectable changes such as pharmacological or adaptive responses, the NOAEL specifically excludes non-adverse effects and identifies the highest dose without biologically or statistically significant harmful outcomes. In contrast, the (LOAEL) marks the lowest dose at which a statistically or biologically significant is observed, effectively serving as the upper boundary for the NOAEL in dose-response analyses. The NOAEL thus defines the threshold below which no harm occurs, whereas the LOAEL indicates the onset of , often used when a clear NOAEL cannot be established and requiring additional factors in risk assessments. NOAEL is the preferred and standard term in contemporary regulatory toxicology, though synonyms such as "no-observed-toxic-effect level" (NOTEL) have appeared in older guidelines and specific contexts like pesticide evaluations, where NOTEL similarly denotes the absence of toxic effects but is less commonly employed today. For instance, an elevation in liver enzyme levels induced by a drug, without accompanying histopathological changes or clinical harm, might qualify as an observable effect under NOEL criteria but would not disqualify a dose as the NOAEL if deemed non-adverse.

Historical Development

Origins in Toxicology

The concept of the no-observed-adverse-effect level (NOAEL), defined as the highest exposure level at which no adverse effects are observed in a study, emerged in the mid-20th century amid heightened concerns over widespread chemical exposures following World War II. The postwar proliferation of synthetic pesticides, such as DDT, and industrial chemicals raised alarms about human and environmental health risks, prompting expanded toxicological research to evaluate safe exposure thresholds. This period saw a shift from acute poisoning studies to chronic low-dose assessments, driven by incidents like pesticide contamination in agriculture and worker exposures in manufacturing. Key early influences on NOAEL stemmed from advancements in dose-response modeling during the and , where it served as a practical threshold concept for interpreting data. Building on Haber's rule (formulated in but increasingly applied in mid-century studies), which posits that depends on the product of concentration and exposure time (C × t = k), researchers used parabolic or sigmoidal curve extrapolations to estimate safe doses below observable effects. These models, often involving log-dose transformations, allowed toxicologists to delineate regions of no effect from adverse responses in experimental data, laying the groundwork for NOAEL as a benchmark in non-cancer evaluations. NOAEL was initially applied in animal bioassays to identify safe thresholds for chemicals, predating its formal regulatory adoption, including in early U.S. (FDA) evaluations of food additives during the 1950s. In these and other studies, doses were selected to span from no-effect levels to those producing mild , enabling the determination of margins of through applied factors to human exposures. For instance, subchronic feeding trials assessed organ weights, , and clinical signs to pinpoint doses without adverse outcomes, informing decisions under the 1958 Food Additives Amendment. Informal references to NOAEL-like thresholds first appeared in toxicology literature around the 1960s, for example in a 1963 analysis by Weil and McCollister of NOAELs in short- and long-term feeding studies, evolving from "maximum tolerated dose" (MTD) concepts that emphasized doses causing minimal effects short of severe toxicity or death. The MTD, established by the National Cancer Institute in the early 1970s for carcinogenesis bioassays and formalized in 1976 guidelines, defined the upper limit as a dose reducing body weight gain by no more than 10% without mortality or significant toxicity, with NOAEL identified at the next lower level lacking adverse signs. This progression reflected a growing emphasis on quantifiable, non-lethal endpoints in safety assessments.

Evolution in Regulatory Frameworks

The U.S. Environmental Protection Agency (EPA) began adopting the no-observed-adverse-effect level (NOAEL) in the late 1970s and 1980s as part of efforts to standardize non-cancer risk assessments, particularly through the development of the Integrated Risk Information System (IRIS). Established in 1985, IRIS formalized the use of NOAEL as the point of departure for deriving reference doses (RfD), which estimate safe exposure levels by applying uncertainty factors to account for interspecies and intraspecies variability. This approach marked a shift toward quantitative risk assessment for environmental chemicals, building on earlier qualitative methods in toxicology. Internationally, the (WHO) and (FAO) integrated NOAEL into their (ADI) framework during the 1970s via the Joint FAO/WHO Meeting on Pesticide Residues (JMPR), where it served as the basis for establishing lifetime safe intake levels for food additives and pesticides. In the , NOAEL gained prominence in the 1990s through guidelines from the Scientific Committee on Food (SCF), which informed regulatory practices for chemical safety prior to the establishment of the (EFSA) in 2002. Key regulatory milestones further entrenched NOAEL's role. In 1983, EPA's guidelines on under standards emphasized NOAEL identification in repeat-dose studies to support hazard assessment. The U.S. (FDA) clarified its application in 2005 guidance for estimating safe starting doses in clinical trials, explicitly distinguishing NOAEL—defined as the highest dose with no adverse effects—from the broader no-observed-effect level (NOEL). By the 1990s, NOAEL had become central to the Organisation for Economic Co-operation and Development (OECD) test guidelines, such as Test No. 408 for repeated-dose 90-day oral toxicity studies (adopted 1981, updated 1998) and Test No. 422 for combined repeated-dose and reproduction screening (adopted 1996), which require reporting NOAELs to inform risk characterization. These harmonized standards, adopted by OECD's 38 member countries and influencing regulations in over 100 nations through mutual acceptance agreements, promoted global consistency in chemical testing and safety evaluations.

Determination and Methodology

Experimental Study Design

Experimental study designs for determining the no-observed-adverse-effect level (NOAEL) primarily involve toxicity testing in animal models to identify dose thresholds without adverse effects, adhering to standardized protocols such as those from the (OECD) and (GLP) principles to ensure data reliability and reproducibility. Key study types include acute, subchronic, and tests conducted in or other mammals. Acute studies, such as the OECD Test Guideline 425 up-and-down procedure, assess single or short-term exposures (typically 14 days observation) via oral, dermal, or inhalation routes to establish initial safety margins, though they contribute less directly to NOAEL than repeat-dose designs. Subchronic studies, exemplified by OECD Test Guideline 408, involve repeated daily dosing for 90 days in (preferably rats) to evaluate effects from prolonged subchronic exposure, providing critical data for intermediate-duration risk assessments. Chronic studies under OECD Test Guideline 452 extend dosing to 6–24 months (typically 12 months in ) to detect long-term effects, including potential carcinogenicity when combined with other endpoints, and are essential for lifetime exposure evaluations. These designs follow GLP standards, which mandate quality assurance, documentation, and facility compliance to support regulatory submissions. Dose selection in these studies typically includes three to four dose levels plus a concurrent control group, with administration via gavage, diet, or to mimic relevant exposure routes. Doses are spaced logarithmically using 2- to 4-fold intervals (e.g., 10, 30, 100 mg/kg/day) to efficiently bracket the expected threshold for adverse effects while minimizing animal use and capturing dose-response relationships. The highest dose aims to induce minimal without causing death or severe suffering, often limited to 1,000 mg/kg/day, informed by prior range-finding studies. Endpoints monitored encompass a comprehensive battery of observations to detect subtle adverse effects. Clinical signs include daily general checks and weekly detailed assessments of , , eyes, and mucous membranes. Body weight and (and water) consumption are recorded weekly during subchronic studies and monthly in chronic ones. involves (e.g., , leukocyte counts), (e.g., liver enzymes, glucose, ), and optional (e.g., , protein). At termination, all animals undergo necropsy for organ weights (e.g., liver, kidneys, brain, heart, reproductive organs) and gross , followed by of major tissues in control and high-dose groups, extending to lower doses if effects are observed. and developmental effects, such as indices or fetal anomalies, may be incorporated in extended designs but are not primary in standard protocols. To ensure statistical power for detecting biologically relevant effect sizes, studies use at least 20–50 animals per sex per dose group, with rodents (e.g., 10–20 per sex in subchronic, up to 50 per sex in chronic) providing sufficient sensitivity for 10–20% changes in endpoints like body weight or organ weights. This group size balances ethical considerations with the need to identify adverse effects reliably under GLP-compliant conditions.

Identification and Analysis Techniques

The identification of the no-observed-adverse-effect level (NOAEL) from toxicological study data involves a systematic analysis of dose-response relationships to pinpoint the highest dose at which no biologically relevant adverse effects are observed. This process begins with the collection and preprocessing of endpoint data, such as organ weights, clinical observations, or biochemical markers, from experimental groups exposed to graduated doses alongside a control group. Data normalization, including adjustments for batch effects or conversion to percentage changes relative to controls, ensures comparability across groups. A key initial step is to plot the dose-response curve, which visualizes the relationship between administered doses and measured responses, often using parametric models like the log-logistic function fitted to the data via . This graphical representation aids in identifying trends and potential inflection points where effects emerge. Following visualization, statistical tests are applied to quantify differences: analysis of variance (ANOVA) first assesses overall dose-related effects across groups, and if significant (p ≤ 0.05), post-hoc tests such as Dunnett's procedure compare each treatment group to the control to isolate specific dose impacts. The lowest observed adverse effect level (LOAEL) is then defined as the lowest dose exhibiting a statistically significant relative to the control. The NOAEL is determined as the highest dose immediately below the LOAEL where no significant adverse effects are detected, typically requiring p > 0.05 in , though biological relevance supersedes pure statistical thresholds. For instance, an is calculated to evaluate magnitude, defined as: Effect size=xˉtreated−xˉcontrolscontrol\text{Effect size} = \frac{\bar{x}_{\text{treated}} - \bar{x}_{\text{control}}}{s_{\text{control}}} where xˉtreated\bar{x}_{\text{treated}} and xˉcontrol\bar{x}_{\text{control}} are the mean responses in the treated and control groups, respectively, and scontrols_{\text{control}} is the standard deviation of the control. Toxicologist judgment is essential, integrating contextual factors like study duration and endpoint sensitivity; for example, a 5% decrease in body weight may qualify as adverse in chronic exposure studies due to implications for overall but not in acute settings where transient changes are less concerning. Specialized software facilitates automation, such as R packages like drc for dose-response modeling and NOAEL estimation, or tools like DoseResponseDesigns for planning and analysis, enhancing reproducibility in regulatory contexts.

Applications in Risk Assessment

Pharmaceutical and Drug Safety

In the preclinical phases of drug development, the no-observed-adverse-effect level (NOAEL) derived from toxicology studies in rodents and non-rodents serves as a foundational metric for establishing the safe starting dose in Phase I human clinical trials. These studies, typically conducted under Good Laboratory Practice (GLP) conditions, identify the highest dose at which no adverse effects are observed, allowing for the calculation of the human equivalent dose (HED) using body surface area scaling from the animal NOAEL, followed by division by a safety factor (typically 10) to account for uncertainties such as intraspecies variability. This approach ensures a conservative margin of safety, with the starting dose often further adjusted based on pharmacokinetic data to achieve sub-therapeutic exposures initially. The integration of NOAEL into international regulatory frameworks, such as the International Council for Harmonisation (ICH) M3(R2) guideline, underscores its role in evaluating the —the ratio between the effective dose and the dose causing —and in qualifying impurities during . Under ICH M3(R2), NOAEL data from repeat-dose studies inform exposure margins, recommending that starting clinical doses not exceed 1/50th of the NOAEL exposure in certain exploratory trials to monitor potential reversible toxicities. For impurities, NOAEL values may support qualification thresholds per ICH Q3A and Q3B guidelines when specific data are available, ensuring that residual levels do not pose undue risk before advancing to later clinical phases. The U.S. (FDA) mandates the inclusion of NOAEL data from preclinical studies in (IND) applications to assess the potential for safe exposure. Post-2005 FDA guidance emphasizes the importance of expert judgment in defining adversity to accurately determine the NOAEL, focusing on effects that would be unacceptable at the initial clinical dose rather than minor adaptive changes. For instance, in the development of a new , a NOAEL of 100 mg/kg from a repeat-dose study in dogs might translate to a of approximately 54 mg/kg using body surface area scaling, and a starting dose of approximately 5 mg/kg after applying the safety factor of 10, providing a broad safety margin while allowing escalation based on emerging clinical data. This process exemplifies how NOAEL bridges nonclinical findings to safety evaluation, minimizing risks in early therapeutic testing.

Environmental and Chemical Regulation

The no-observed-adverse-effect level (NOAEL) plays a central role in environmental and chemical regulation by informing the derivation of safe exposure limits for contaminants and industrial chemicals, ensuring protection against long-term population-level risks from persistent exposures. In the United States, the Environmental Protection Agency (EPA) uses NOAEL to calculate the reference dose (RfD), an estimate of a daily oral exposure to the human population that is likely to be without appreciable risk of deleterious effects during a lifetime. The RfD is derived by dividing the NOAEL—typically from —by uncertainty factors (UFs) that account for interspecies differences (usually 10-fold) and intraspecies variability (usually 10-fold), resulting in total UFs of 100 to 1000 depending on data quality and additional sensitivities. NOAEL is integral to pesticide regulation under the Federal Insecticide, Fungicide, and Act (FIFRA), where the EPA requires data to establish safe use levels, often deriving population-adjusted doses (PADs) from NOAELs for dietary and other exposures during registration and review processes. Similarly, in international assessments, the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) establishes the (ADI) by dividing the NOAEL—identified as the lowest value from the most sensitive species in long-term studies—by a safety factor of 100 to extrapolate to humans. A representative example is the assessment of dioxins, highly persistent environmental contaminants, where the (WHO) derived a tolerable daily intake (TDI) of 1–4 pg TEQ/kg body weight based on NOAELs from chronic studies in rats showing no reproductive or developmental , adjusted by uncertainty factors for human extrapolation. In the , the (EFSA) has applied NOAEL since the early 2000s to set acute reference doses (ARfDs) for plant protection products, using short-term study endpoints divided by safety factors to evaluate single-exposure risks from residues.

Limitations and Alternatives

Challenges and Criticisms

One significant challenge in the application of the no-observed-adverse-effect level (NOAEL) lies in the subjectivity involved in defining what constitutes an , as interpretations can vary based on the specific endpoint measured and the context of the study. For instance, toxicologists may differ on whether subtle physiological changes, such as alterations in levels, qualify as adverse, leading to inconsistencies in NOAEL identification across studies. This subjectivity is particularly evident in the over endocrine disruption, where effects on hormonal systems were increasingly scrutinized as potentially adverse starting in the , prompting regulatory shifts but also highlighting the lack of uniform criteria for classification. Statistical limitations further undermine the reliability of NOAEL determinations, as low-dose effects may go undetected due to insufficient study power, resulting in an overestimation of safe exposure levels. The NOAEL is inherently tied to the tested doses and sample sizes, often failing to capture subtle responses below the identified threshold because of limited statistical sensitivity. Additionally, interspecies variability in toxicokinetics and toxicodynamics necessitates the application of large factors (typically 10-fold or more) when extrapolating animal NOAELs to humans, which can introduce substantial but also amplify uncertainties in risk estimates. Critics argue that the NOAEL approach over-relies on animal data, which may not adequately reflect sensitivity to certain toxicants, potentially leading to underestimation of risks in vulnerable populations. This reliance is particularly problematic for non-threshold carcinogens, where the assumption of a safe dose below the NOAEL does not hold, as even minimal exposures are theorized to carry risk without a identifiable threshold. Reviews from the in the late 2000s emphasized the binary nature of NOAEL, noting that it disregards the and of the dose-response , thereby limiting its utility in comprehensive risk characterization.

Emerging Methodological Advances

Benchmark dose (BMD) modeling represents a key advancement in quantitative , fitting dose-response data to mathematical models to estimate a point of departure that serves as a more statistically robust alternative to the traditional NOAEL. This approach utilizes the full dataset from studies, including continuous endpoints, to derive the BMD—the dose associated with a specified benchmark response (BMR), such as a 10% change in an adverse outcome—and its lower limit (BMDL), which provides a conservative estimate with 95% . By incorporating uncertainty and variability more explicitly, BMD modeling addresses limitations in NOAEL determination, such as dependence on dose spacing and sample size, offering greater precision and across studies. A common formulation in BMD modeling employs the Hill equation for the dose-response relationship, expressed as: response=background+slope×dosehillEC50hill+dosehill\text{response} = \text{background} + \text{slope} \times \frac{\text{dose}^{\text{hill}}}{\text{EC50}^{\text{hill}} + \text{dose}^{\text{hill}}} where the BMD is the dose yielding the predefined BMR (e.g., 10% extra risk above background), and the BMDL is the lower one-sided 95% confidence bound on that dose. Specialized software like PROAST, developed by the Dutch National Institute for Public Health and the Environment (RIVM), facilitates this analysis by implementing model averaging across multiple dose-response families (e.g., exponential, Hill) to select the best fit and compute BMDL values efficiently. In parallel, in vitro and computational toxicology methods are transforming NOAEL prediction by leveraging high-throughput screening (HTS) platforms to evaluate toxicity pathways without relying on whole-animal studies. Recent advances include AI and machine learning models for toxicity prediction, which analyze large datasets to estimate adverse outcomes and points of departure with reduced reliance on traditional testing. The U.S. EPA's ToxCast program, for instance, assays thousands of chemicals across hundreds of cell-based endpoints to generate predictive signatures that correlate with in vivo outcomes, enabling estimation of safe exposure levels through quantitative adverse outcome pathway (qAOP) modeling. These approaches align with the Toxicology in the 21st Century (Tox21) initiative, a collaborative effort by U.S. agencies including the EPA, NIH, and FDA, which prioritizes human cell-based assays and computational tools to identify perturbations in biological pathways relevant to adverse effects, thereby reducing animal use and accelerating safety assessments. Regulatory adoption of these advances has accelerated in recent years; the U.S. EPA began emphasizing BMD modeling in its Integrated Risk Information System (IRIS) assessments around 2012, integrating it as the preferred method for deriving reference doses when sufficient data are available. In 2025, the FDA released a roadmap for phasing out requirements, promoting new approach methodologies (NAMs) to further support alternatives to NOAEL-based assessments. Similarly, in the during the 2020s, there has been a strong push toward integrated approaches to testing and assessment (IATA), as outlined by the European Commission's and guidance, which combine data, predictions, and read-across to inform chemical safety without traditional ; this includes new IATA case studies released by the in October 2025. These methodological shifts directly tackle persistent challenges in NOAEL-based assessments, such as interspecies extrapolation and ethical concerns over , by enhancing mechanistic insight and predictive power.

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  61. https://www.fda.gov/science-research/advancing-alternative-methods-fda/implementing-alternative-methods
  62. https://joint-research-centre.ec.europa.eu/projects-and-activities/reference-and-measurement/european-union-reference-laboratories/eu-reference-laboratory-alternatives-animal-testing-eurl-ecvam/alternative-methods-toxicity-testing/iata-integrated-approaches-testing-and-assessment_en
  63. https://www.thepsci.eu/news-updates/new-oecd-iata-case-studies-illustrate-frameworks-for-chemical-safety-assessment/
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