Challenges and Research Needs for Risk Assessment of Pesticides for Registration in Africa

Risk assessment is necessary for registration and risk management of new pesticides. The aim of this article is to discuss challenges that risk assessors in Africa face when conducting risk assessment of pesticides. Risk assessment requires toxicity assessment, environmental fate studies, and the use of models for occupational, dietary, residential, and environmental exposure assessments. Toxicity studies are very costly with the result that toxicity data used to register pesticides in Africa are often sourced from northern hemisphere countries. Assessors also often use exposure modeling results from the northern hemisphere. This is not an ideal approach as occupational exposure is influenced by agricultural practices, climatic conditions, and other factors. Furthermore, residential exposure models require time-location-activity information, exposure factors, and toxicokinetic rate constants for particular pesticides. Dietary exposure assessment needs accurate and comprehensive local food consumption data. Authorities in African countries should therefore generate the required data, despite these being very costly and tedious. Authorities should also provide guidance on the type of models and standard scenarios for estimating predicted environmental concentrations in various environmental compartments. It is recommended that higher educational institutions in Africa should incorporate risk assessment in general and pesticide toxicity and exposure models in particular in their curricula.     

Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson's disease

Among age-related neurodegenerative diseases, Parkinson's disease (PD) represents the best example for which oxidative stress has been strongly implicated. The etiology of PD remains unknown, yet recent epidemiological studies have linked exposure to environmental agents, including pesticides, with an increased risk of developing the disease. As a result, the environmental hypothesis of PD has developed, which speculates that chemical agents in the environment are capable of producing selective dopaminergic cell death, thus contributing to disease development. The use of environmental agents such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone, paraquat, dieldrin, and maneb in toxicant-based models of PD has become increasingly popular and provided valuable insight into the neurodegenerative process. Understanding the unique and shared mechanisms by which these environmental agents act as selective dopaminergic toxicants is critical in identifying pathways involved in PD pathogenesis. In this review, we discuss the neurotoxic properties of these compounds with specific focus on the induction of oxidative stress. We highlight landmark studies along with recent advances that support the role of reactive oxygen and reactive nitrogen species from a variety of cellular sources as potent contributors to the neurotoxicity of these environmental agents. Finally, human risk and the implications of these studies in our understanding of PD-related neurodegeneration are discussed.     

Quantitative risk assessment for multivariate continuous outcomes with application to neurotoxicology: the bivariate case

The neurotoxic effects of chemical agents are often investigated in controlled studies on rodents, with multiple binary and continuous endpoints routinely collected. One goal is to conduct quantitative risk assessment to determine safe dose levels. Such studies face two major challenges for continuous outcomes. First, characterizing risk and defining a benchmark dose are difficult. Usually associated with an adverse binary event, risk is clearly definable in quantal settings as presence or absence of an event; finding a similar probability scale for continuous outcomes is less clear. Often, an adverse event is defined for continuous outcomes as any value below a specified cutoff level in a distribution assumed normal or log normal. Second, while continuous outcomes are traditionally analyzed separately for such studies, recent literature advocates also using multiple outcomes to assess risk. We propose a method for modeling and quantitative risk assessment for bivariate continuous outcomes that address both difficulties by extending existing percentile regression methods. The model is likelihood based; it allows separate dose-response models for each outcome while accounting for the bivariate correlation and overall characterization of risk. The approach to estimation of a benchmark dose is analogous to that for quantal data without the need to specify arbitrary cutoff values. We illustrate our methods with data from a neurotoxicity study of triethyl tin exposure in rats.     

Human exposure to endocrine disrupters: carcinogenic risk assessment

Human exposure to endocrine disrupters (EDs) is widespread and is considered to pose a growing threat to human health. Recent advances in molecular and genetic research and better understanding of mechanisms of blastic cell transformation have led to efforts to improve cancer risk assessment for populations exposed to this family of xenobiotics. In risk assessment, low dose extrapolation of cancer incidence data from both experimental animals and epidemiology studies has been largely based on models assuming linear correlation at low doses, despite existence of evidence showing otherwise. Another weakness of ED risk assessment is poor exposure data in ecological studies. Those are frequently rough estimates derived from contaminated items of local food basket surveys. Polyhalogenated hydrocarbons are treated as examples. There is growing sense of urgency to develop a biologically based dose response model of cancer risk, integrating emerging data from molecular biology and epidemiology to provide more realistic data for risk assessors, public, public health managers and environmental issues administrators.     

Use of in vivo genetic toxicity data for risk assessment

Mutagenicity studies have been used to identify specific agents as potential carconogens or other human health hazards; however, they have been used minimally for risk assessment or in determining permissible levels of human exposure. The poor predictive value of in vitro mutagenesis tests for carcinogenic activity and a lack of mechanistic understanding of the roles of mutagens in the induction of specific cancers have made these tests unattractive for the purpose of risk assessment. However, the limited resources available for carcinogen testing and large number of chemicals which need to be evaluated necessitate the incorporation of more efficient methods into the evaluation process. In vivo genetic toxicity testing can be recommended for this purpose because in vivo assays incorporate the metabolic activation pathways that are relevant to humans. We propose the use of a multiple end-point in vivo comprehensive testing protocol (CTP) using rodents. Studies using sub-acute exposure to low levels of test agents by routes consistent with human exposure can be a useful adjunct to methods currently used to provide data for risk assessment. Evaluations can include metabolic and pharmacokinetic endpoints, in addition to genetic toxicity studies, in order to provide a comprehensive examination of the mechanism of toxicity of the agent. A parallelogram approach can be used to estimate effects in non-accessible human tissues by using data from accessible human tissues and analogous tissues in animals. A categorical risk assessment procedure can be used which would consider, in order of priority, genetic damage in man, genetic damage in animals that is highly relevant to disease outcome (mutation, chromosome damage), and data from animals that is of less certain relevance to disease. Action levels of environmental exposure would be determined based on the lowest observed effect levels or the highest observed no effect levels, using sub-acute low level exposure studies in rodents. As an example, the known genotoxic effects of benzene exposure at low levels in man and animals are discussed. The lowest observed genotoxic effects were observed at about 1–10 parts per million for man and 0.04–0.1 parts per million in subacute animal studies. If genetic toxicity is to achieve a prominent role in evaluating carcinogens and characterizing germ-cell mutagens, minimal testing requirements must be established to ascertain the risk associated with environmental mutagen exposure. The use of the in vivo approach described here should provide the information needed to meet this goal. In addition, it should allow truly epigenetic or non-genotoxic carcinogens to be distinguished from the genotoxic carcinogens that are not detected by in vitro methods.     

Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies

Neurological disorders are common, costly, and can cause enduring disability. Although mostly unknown, a few environmental toxicants are recognized causes of neurological disorders and subclinical brain dysfunction. One of the best known neurotoxins is methylmercury (MeHg), a ubiquitous environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. In the aquatic environment, MeHg is accumulated in fish, which represent a major source of human exposure. Although several episodes of MeHg poisoning have contributed to the understanding of the clinical symptoms and histological changes elicited by this neurotoxicant in humans, experimental studies have been pivotal in elucidating the molecular mechanisms that mediate MeHg-induced neurotoxicity. The objective of this mini-review is to summarize data from experimental studies on molecular mechanisms of MeHg-induced neurotoxicity. While the full picture has yet to be unmasked, in vitro approaches based on cultured cells, isolated mitochondria and tissue slices, as well as in vivo studies based mainly on the use of rodents, point to impairment in intracellular calcium homeostasis, alteration of glutamate homeostasis and oxidative stress as important events in MeHg-induced neurotoxicity. The potential relationship among these events is discussed, with particular emphasis on the neurotoxic cycle triggered by MeHg-induced excitotoxicity and oxidative stress. The particular sensitivity of the developing brain to MeHg toxicity, the critical role of selenoproteins and the potential protective role of selenocompounds are also discussed. These concepts provide the biochemical bases to the understanding of MeHg neurotoxicity, contributing to the discovery of endogenous and exogenous molecules that counteract such toxicity and provide efficacious means for ablating this vicious cycle.     

Analytical methods for biological monitoring of exposure to pesticides: a review

Synthetic pesticides have been used since in the early to mid twentieth century. In the US alone, over 800 pesticide active ingredients are formulated in about 21,000 different commercial products. Although many public health benefits have been realized by the use of pesticides, their potential impact on the environment and public health is substantial. For risk assessment studies, exposure assessment is an integral component, which has unfortunately, often been weak or missing. In the past several decades, researchers have proposed to fill these missing data gaps using biological monitoring of specific markers related to exposures. In this paper, we present a review of existing analytical methodology for the biological monitoring of exposure to pesticides. We also present a critical assessment of the existing methodology and explore areas in which more research is needed.     

Utilization of Neural Stem Cell-Derived Models to Study Anesthesia-Related Toxicity and Preventative Approaches

Early-life stress has been shown in both preclinical and clinical studies to cause neuroanatomical and biological alterations and disruptions in homeostasis. These alterations can lead to dysfunction in critical regulatory systems and concomitant increases in risk for the development of pathology. The existing data from research using in vivo animal models have implicated some general anesthetics as being toxic to the developing brain and causing cognitive deficits later in life. Because of obvious limitations, it is not possible to thoroughly explore the effects of early-life stress—e.g., prolonged exposure to anesthetic agents—on neurons in vivo in human infants or children. However, the availability of stem cell-derived models, especially human embryonic neural stem cells, along with their capacity for proliferation and ability to differentiate, has provided a potentially invaluable tool for examining the developmental effects of anesthetic agents in vitro. This review focuses on how embryonic neural stem cells, when combined with biochemical, pathological, and pharmacokinetic assessments, might serve as a bridging platform to provide the most expeditious approaches toward decreasing the uncertainty in extrapolating preclinical data to the human condition. This review presents key concepts in stem cell biology with respect to the nervous system, presents an overview of neural development, and summarizes the involvement of neural cell types in developmental neurotoxicity associated with anesthetic exposure.     

Life cycle human health impacts of 875 pesticides

Purpose

Residues in field crops grown and harvested for human consumption are the main contributor to overall human exposure toward agricultural pesticides for the general population. However, exposure from crop residues is currently not considered in life cycle assessment practice. We therefore present a consistent framework for characterizing human toxicological impacts associated with pesticides applied to agricultural crops in the frame of life cycle impact assessment based on state-of-the-art data and methods.

Methods

We combine a dynamic multicrop plant uptake model designed for evaluating human exposure to residues for a wide range of pesticide-crop combinations with latest findings of pesticide dissipation kinetics in crops and post-harvest food processing. Outcome is a set of intake fractions and characterization factors for 875 organic pesticides and six major food crops along with specific confidence intervals for each factor.

Results and discussion

Intake fractions aggregating exposure via crop residues and exposure via fractions lost to air and soil for pesticides applied to agricultural crops vary between 10^?8 and 10^?1 kg intake per kilogram applied as a function of pesticide and crop. Intake fractions are typically highest for lettuce and tomato and lowest for potato due to differences in application times before crop harvest and soil as additional barrier for uptake into potato tubers. Uncertainty in intake fractions is mainly associated with dissipation dynamics in crops, where results demonstrate that using pesticide- and crop-specific data is crucial. Combined with the uncertainty in effect modeling, characterization factors per pesticide and crop show squared geometric mean standard deviations ranging from 38 to 15,560 over a variability range across pesticide-crop combinations of 10 orders of magnitude.

Conclusions

Our framework is operational for use in current life cycle impact assessment models, is made available for USEtox, and closes an important gap in the assessment of human exposure to pesticides. For ready use in life cycle assessment studies, we present pesticide-crop combination-specific characterization factors normalized to pesticide mass applied and provide default data for application times and loss due to post-harvest food processing. When using our data, we emphasize the need to consult current pesticide regulation, since each pesticide is registered for use on certain crops only, which varies between countries.

     

The Value of Human Testing of Pesticides

Recently, the issue of using human volunteers as subjects for studying the potential toxicity of pesticides has received public attention through the media and subsequently in the regulatory arena. The debate has focused on whether such studies are ethical per se and if data from these investigations should be used for regulatory decisions. The precipitating event that prompted the current debate was the enactment of the Food Quality Protection Act (FQPA) of 1996. The FQPA, which amended the two laws governing the regulation of pesticides in the United States, requires the Environmental Protection Agency to reassess all of the nearly 10,000 tolerances (maximum allowable residues in food) and exemptions from tolerances that were in place when the law went into effect. When reassessing tolerances the U.S. Environmental Protection Agency (USEPA) reviews the data, including toxicology, available on each pesticide to determine if they are adequate to allow the Agency to make the necessary safety finding. Historically, it had been considered acceptable to conduct and use data from studies of exposure to chemicals (including pesticides) of human volunteers if these studies were conducted according to specific criteria as outlined in the Helsinki Declaration and Common Rule. Now this philosophy is being challenged and the USEPA is faced with answering the question of whether pesticides should be viewed as different, from an ethical standpoint, from other chemicals, and how such data should be used in the risk assessment process. The following paper makes an argument for the use of human volunteer testing of pesticides applying the logic that, if one wants to protect humans from the potential harm that may occur from eating foods containing pesticides, one must use the best possible data available. There can be little doubt that the best data for predicting the toxicity of a chemical in humans is to obtain and use human data, as long as it is obtained in an ethical manner.     

Human blood and environmental media screening method for pesticides and polychlorinated biphenyl compounds using liquid extraction and gas chromatography-mass spectrometry analysis

Screening assessment methods have been developed for semi- and non-volatile persistent organic pollutants (POPs) for human blood and solid environmental media. The specific methodology is developed for measuring the presence of "native" compounds, specifically, a variety of organochlorine pesticides (OCPs), organophosphate pesticides (OPPs), and for polychlorinated biphenyls (PCBs). The method is demonstrated on anonymous Red Cross blood samples as well as two potential environmental sources, tracked in soil and dog hair. This work is based on previously developed methods for semi-volatile hydrocarbon exposure from fuels usage and similarly employs liquid solvent extraction, evaporative volume reduction. and subsequent specialized gas chromatography-mass spectrometry analysis (GC-MS). Standard curves, estimates of recovery efficiency, and specific GC-MS SIM quantification methods were developed for common pesticides including diazinon. aldrin, chlorpyrifos, malathion, dieldrin, DDT, permethrin, cyhalothrin, and cypermethrin, and for seven selected PCBs. Trace levels of certain PCBs and pesticides such as permethrin, dieldrin, malathion, lindane, diazinon, and chlorpyrifos were tentatively identified in anonymous blood samples as well as in two potential environmental sources. tracked in soil and dog hair. The method provides a simple screening procedure for various media and a variety of common organic pollutants without extensive sample preparation. It is meant to complement and augment data from more specific or complex methodology, to provide initial broad spectrum guidance for designing targeted experiments, and to provide confirmatory evidence for the usual metabolic biomarker measurements made to assess human exposure.     

Investigate the chronic neurotoxic effects of diquat

Chronic exposure to agricultural chemicals (pesticides/herbicides) has been shown to induce neurotoxic effects or results in accumulation of various toxic metabolic by-products. These substances have the relevant ability to cause or increase the risk for neurodegeneration. Diquat is an herbicide that has been extensively used in the United States of America and other parts of the world. Diquat is constantly released into the environment during its use as a contact herbicide. Diquat structurally resembles 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and paraquat. Rotenone, paraquat, maneb and MPTP reproduce features of movement disorders in experimental animal models. Based on the structural similarity to other neurotoxins, chronic exposure of diquat can induce behavioral and neurochemical alterations associated with dopaminergic neurotoxicity. However, in the present study, diquat unlike other neurotoxins (rotenone, 6-hydroxydopamine, MPTP, paraquat and maneb) did not induce dopamine depletion in the mouse striatum. Although, notable exacerbation in motor impairment (swimming score, akinesia and open field) were evident that may be due to the decreased dopamine turnover and mild nigrostriatal neurodegeneration. These data indicate that, despite the apparent structural similarity to other dopaminergic neurotoxins, diquat did not exert severe deleterious effects on dopamine neurons in a manner that is unique to rotenone and MPTP.     

Role of α2‐macroglobulin in regulating amyloid β‐protein neurotoxicity: protective or detrimental factor?

alpha2-Macroglobulin (alpha2M) has been identified as a carrier protein for beta-amyloid (Abeta) decreasing fibril formation and affecting the neurotoxicity of this peptide. The alpha2-macroglobulin receptor/low density lipoprotein receptor related protein (LRP) is involved in the internalization and degradation of the alpha2M/Abeta complexes and its impairment has been reported to occur in Alzheimer's disease. Previous studies have shown alpha2M to determine an enhancement or a reduction of Abeta toxicity in different culture systems. In order to clarify the role of alpha2M in Abeta neurotoxicity, we challenged human neuroblastoma cell lines with activated alpha2M in combination with Abeta. Our results show that in neuroblastoma cells expressing high levels of LRP, the administration of activated alpha2M protects the cells from Abeta neurotoxicity. Conversely, when this receptor is not present alpha2M determines an increase in Abeta toxicity as evaluated by MTT and TUNEL assays. In LRP-negative cells transfected with the full-length human LRP, the addition of activated alpha2M resulted to be protective against Abeta-induced neurotoxicity. By means of recombinant proteins we ascribed the neurotoxic activity of alpha2M to its FP3 fragment which has been previously shown to bind and neutralize transforming growth factor-beta. These studies provide evidence for both a neuroprotective and neurotoxic role of alpha2M regulated by the expression of its receptor LRP.     

Improving Risk Assessment: Priorities for Epidemiologic Research

The Epidemiology Work Group at the Workshop on Future Research for Improving Risk Assessment Methods, Of Mice, Men, and Models, held August 16 to 18, 2000, at Snowmass Village, Aspen, Colorado, concluded that in order to improve the utility of epidemiologic studies for risk assessment, methodologic research is needed in the following areas: (1) aspects of epidemiologic study designs that affect doseresponse estimation; (2) alternative methods for estimating dose in human studies; and (3) refined methods for dose-response modeling for epidemiologic data. Needed research in aspects of epidemiologic study design includes recognition and control of study biases, identification of susceptible subpopulations, choice of exposure metrics, and choice of epidemiologic risk parameters. Much of this research can be done with existing data. Research needed to improve determinants of dose in human studies includes additional individual-level data (e.g., diet, co-morbidity), development of more extensive human data for physiologically based pharmacokinetic (PBPK) dose modeling, tissue registries to increase the availability of tissue for studies of exposure/dose and susceptibility biomarkers, and biomarker data to assess exposures in humans and animals. Research needed on dose-response modeling of human studies includes more widespread application of flexible statistical methods (e.g., general additive models), development of methods to compensate for epidemiologic bias in dose-response models, improved biological models using human data, and evaluation of the benchmark dose using human data. There was consensus among the Work Group that, whereas most prior risk assessments have focused on cancer, there is a growing need for applications to other health outcomes. Developmental and reproductive effects, injuries, respiratory disease, and cardiovascular disease were identified as especially high priorities for research. It was also a consensus view that epidemiologists, industrial hygienists, and other scientists focusing on human data need to play a stronger role throughout the risk assessment process. Finally, the group agreed that there was a need to improve risk communication, particularly on uncertainty inherent in risk assessments that use epidemiologic data.     

Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the Kappa opioid receptor

Methamphetamine (METH) is a psychostimulant with high abuse potential and severe neurotoxicity. Recent studies in animal models have indicated that METH can impair the blood–brain barrier (BBB), suggesting that some of the neurotoxic effects resulting from METH abuse could be due to barrier disruption. We report here that while chronic exposure to METH disrupts barrier function of primary human brain microvascular endothelial cells (HBMECs) and human umbilical vein endothelial cells (HUVECs), an early pro-survival response is observed following acute exposure by induction of autophagic mechanisms. Acute METH exposure induces an early increase in Beclin1 and LC3 recruitment. This is mediated through inactivation of the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70S6K pathway, and upregulation of the ERK1/2. Blockade of Kappa opioid receptor (KOR), and treatment with autophagic inhibitors accelerated METH-induced apoptosis, suggesting that the early autophagic response is a survival mechanism for endothelial cells and is mediated through the kappa opioid receptor. Our studies indicate that kappa opioid receptor can be therapeutically exploited for attenuating METH-induced BBB dysfunction.     

Molecular mechanisms of pesticide-induced neurotoxicity: Relevance to Parkinson's disease

Pesticides are widely used in agricultural and other settings, resulting in continued human exposure. Pesticide toxicity has been clearly demonstrated to alter a variety of neurological functions. Particularly, there is strong evidence suggesting that pesticide exposure predisposes to neurodegenerative diseases. Epidemiological data have suggested a relationship between pesticide exposure and brain neurodegeneration. However, an increasing debate has aroused regarding this issue. Paraquat is a highly toxic quaternary nitrogen herbicide which has been largely studied as a model for Parkinson's disease providing valuable insight into the molecular mechanisms involved in the toxic effects of pesticides and their role in the progression of neurodegenerative diseases. In this work, we review the molecular mechanisms involved in the neurotoxic action of pesticides, with emphasis on the mechanisms associated with the induction of neuronal cell death by paraquat as a model for Parkinsonian neurodegeneration.     

Issues in Exposure and Dose Assessment for Epidemiology and Risk Assessment

Epidemiologic studies have been effective in identifying human environmental and occupational hazards. However, most epidemiologic data has been difficult to use in quantitative risk assessments because of the vague specification of exposure and dose. Toxicologic animal studies have used applied doses (quantities administered, or exposures with fixed duration) and well characterized end points to determine effects. However, direct use of animal data in human risk assessment has been limited by uncertainties in the extrapolation. The applied dose paradigm of toxicology is not suited for cross species extrapolation, nor for use in epidemiology as a dose metric because of the complexity of human exposures. Physiologically based pharmacokinetic (PBPK) modeling can estimate the time course of tissue concentrations in humans, given an exposure-time profile, and it has been used for extrapolating findings from animals to humans. It is proposed that human PBPK modeling can be used in appropriately designed epidemiologic studies to estimate tissue concentrations. Secondly, tissue time courses can be used to form dose metrics based on the type and time course of adverse effects. These dose metrics will strengthen the determination of epidemiologic dose-response relationships by reducing misclassification. Findings from this approach can be readily integrated into quantitative risk assessment.     

Environmental Risk of Pesticides: Applying the DelAzulPestRisk Model to Freshwaters of an Agricultural Area of Argentina

DelAzulPestRisk is a risk-based chemical ranking model based on human and local biota toxicities that estimates the integrated risk of pesticides in water from their extensive (concentration, risk) and intensive (persistence, bioaccumulation) chemical properties. The model is built on two modules: human health risk factor (estimated based on the probabilistic cancer and non-cancer health risk by using U.S. Environmental Protection Agency models applied to a bathing exposure scenario) and biota health risk factor (quantified on the basis of the probabilistic toxicity exposure ratio –PEC/PNEC– for three local representatives of water biota multiplied by an amplification factor supported by the persistence and bioaccumulation potential). The model was applied to shallow creeks of Tres Arroyos County, Argentina, which flow across wheat and soybean agricultural lands, and in whose waters were detected many organochlorine pesticides (α, γ, y, δ-HCH, aldrin, heptachlor, γ-chlordane, endosulfan, endosulfan sulphate, dieldrin, and DDD). Dieldrin, aldrin, and heptachlor generated the worst potential effects—due mainly to the cancer and non-cancer dermal health risk—although this was not a significant environmental threat. DelAzulPestRisk is a screening assessment tool for water management purposes that become useful in countries lacking efficient water quality control systems.     

Breast cancer risk in atomic bomb survivors from multi-model inference with incidence data 1958–1998

Breast cancer risk from radiation exposure has been analyzed in the cohort of Japanese a-bomb survivors using empirical models and mechanistic two-step clonal expansion (TSCE) models with incidence data from 1958 to 1998. TSCE models rely on a phenomenological representation of cell transition processes on the path to cancer. They describe the data as good as empirical models and this fact has been exploited for risk assessment. Adequate models of both types have been selected with a statistical protocol based on parsimonious parameter deployment and their risk estimates have been combined using multi-model inference techniques. TSCE models relate the radiation risk to cell processes which are controlled by age-increasing rates of initiating mutations and by changes in hormone levels due to menopause. For exposure at young age, they predict an enhanced excess relative risk (ERR) whereas the preferred empirical model shows no dependence on age at exposure. At attained age 70, the multi-model median of the ERR at 1 Gy decreases moderately from 1.2 Gy⁻¹ (90% CI 0.72; 2.1) for exposure at age 25 to a 30% lower value for exposure at age 55. For cohort strata with few cases, where model predictions diverge, uncertainty intervals from multi-model inference are enhanced by up to a factor of 1.6 compared to the preferred empirical model. Multi-model inference provides a joint risk estimate from several plausible models rather than relying on a single model of choice. It produces more reliable point estimates and improves the characterization of uncertainties. The method is recommended for risk assessment in practical radiation protection.