P. Michael Bolger

Application of the Margin of Exposure (MoE) approach to substances in food that are genotoxic and carcinogenic: EXAMPLE: Acrylamide (CAS No. 79-06-1)

Acrylamide (CH(2)CHCONH(2), CAS Registry No. 79-06-1) is an industrial chemical used since the 1950s as a chemical intermediate in the production of polyacrylamides, which are used as flocculants for clarifying drinking-water and other industrial applications. The neurotoxicity of acrylamide in humans is well known from occupational and accidental exposures. In addition, experimental studies with acrylamide in animals have shown reproductive, genotoxic and carcinogenic properties. Acrylamide may be formed when foods, particularly those that are high in carbohydrates and low in protein, are subjected to high temperatures during cooking or other thermal processing.

A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens

Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice. To address this risk assessment need, a committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute conducted a multisector workshop in late 2009 to discuss available literature, different methodologies, and a proposed framework. The proposed framework provides a decision tree and guidance for cancer risk assessments for less-than-lifetime exposures based on current knowledge of mode of action and dose-response. Available data from rodent studies and epidemiological studies involving less-than-lifetime exposures are considered, in addition to statistical approaches described in the literature for evaluating the impact of changing the dose rate and exposure duration for exposure to carcinogens. The decision tree also provides for scenarios in which an assumption of potential carcinogenicity is appropriate (e.g., based on structural alerts or genotoxicity data), but bioassay or other data are lacking from which a chemical-specific cancer potency can be determined. This paper presents an overview of the rationale for the workshop, reviews historical background, describes the proposed framework for assessing less-than-lifetime exposures to potential human carcinogens, and suggests next steps.

Lead in Women’s and Children’s Vitamins

A survey was conducted to determine the extent of lead (Pb) contamination in vitamins labeled for use by women and children. The Pb content of 324 multivitamin-mineral products was determined using microwave assisted nitric acid digestion and inductively coupled plasma mass spectrometry. Cryogenic grinding was used to composite soft samples such as oil filled capsules and candy-like products such as gummies and jelly beans. Estimates of Pb exposures from consumption of these products were derived for four population groups: young children (0-6 yrs), older children (7+ yrs), pregnant or lactating women, and adult women. The estimated median and maximum Pb exposures were 0.123 and 2.88 microg/day for young children, 0.356 and 1.78 microg/day for older children, 0.845 and 8.97 microg/day for pregnant and lactating women, and 0.842 and 4.92 microg/day for adult women. The overall median value for Pb exposure was 0.576 microg/day. Five samples would have provided exposures that exceeded 4 microg/day. Estimates of exposures were assessed with respect to safe/tolerable exposure levels that have been developed for the specific age and sex groups. These safe/tolerable levels are referred to as the provisional total tolerable intake levels (PTTI) and are 6, 15, 25, and 75 microg Pb/day for young children, older children, pregnant or lactating women, and adult women, respectively. Estimates of Pb exposures were below the PTTI levels for the four population groups. Median and maximum values were used instead of the mean and standard deviation because of the skewed distribution of results toward lower mass fraction and exposure.

Hazard Assessment of Ackee Fruit (Blighia sapida)

Ackee toxicity is associated with consumption of the fruit of the tree Blighia sapida. The problem is endemic in Jamaica, and a number of cases have been reported in the U.S. among Jamaican immigrants. Illness is associated with the method of preparation of the fruit and its ripeness. Malnourished individuals and children appear to be the most susceptible. Levels of the toxic compound, hypoglycin, which are found in the arils and seeds of the fruit, significantly decrease in the arils with ripeness (from 1000 ppm to <0.1 ppm). Symptoms of ackee poisoning in humans occur 6 to 48 hours after ingestion and include vomiting, muscular and mental exhaustion, hypoglycemia, coma and death. Intravenous glucose relieves the hypoglycemia. The most likely mechanism of action occurs through the incorporation of hypoglycin into fatty acid metabolic pathways. Hypoglycin or its primary metabolite methylenecyclopropyl-acetyl-CoA inhibits the oxidation of fatty acids and leucine and the activity of acyl-CoA dehydrogenases....

A pooled analysis of the Iraqi and Seychelles methylmercury studies

Abstract Several epidemiology studies have investigated the impact of maternal exposure to methylmercury (MeHg) on childhood development of the central nervous system (CNS). In the present report, data from the Iraqi episode that occurred in 1970 from contaminated grain are integrated with those from a more recent study of a population with a high fish intake in the Seychelles Islands. The latter study had many more subjects whose mercury hair levels that were much lower and more representative of levels typically found in consumers whose MeHg exposure is from fish. The age of onset of talking (AOT), the age of onset of walking (AOW) and a combined measure (CM) that integrated the two were used as common scales of MeHg effect for the two studies. The first step of the analyses involved the construction of separate two‐dimensional cumulative frequency tables for each study for different groups spanning the range of hair levels and observed effect for each measure. Models were then fit to the values in the tables that were constructed from four components: (1) A dose‐effect function that related hair MeHg to the effect measure; (2) a frequency distribution describing population variability; (3) parameters to represent dose‐independent influences on effect; and (4) parameters to represent study dependent influences on effect. When the four submodels were assembled, a series of 1092 candidate models resulted which contained 3 to 7 parameters (e.g., slope, standard‐deviation, dose‐independent age of talking) whose value could be adjusted to improve the fit. After optimizing the fit of each model, a weighting algorithm that rewards for fit and penalizes for the number of parameters in the model was used to identify the best 200 models. The same algorithm was then used to assign a probability to each model in a probability tree. A two‐dimensional Monte‐Carlo simulation using the resulting function in combination with exposure values typical of U.S. consumers yielded predicted delays in AOT, AOW, and CM attributable to fish consumption in a variable and uncertain range of 0.000 to 1 day.

Global burden of late-stage chronic kidney disease resulting from dietary exposure to cadmium, 2015

Abstract Chronic exposures to cadmium (Cd) are associated with reduced glomerular filtration rate (GFR), increasing the risk of chronic kidney disease (CKD). In support of the World Health Organization (WHO)’s initiative to estimate the global burden of foodborne diseases, a risk assessment was performed to estimate the Disability‐Adjusted Life Years (DALYs) due to late‐stage CKD associated with dietary exposures to cadmium. Using the distribution of population GFRs, the prevalence of CKD was calculated as the proportion of humans whose GFR fall in the ranges corresponding to Stage 4 or Stage 5 CKD. The increase in the CKD prevalence due to cadmium exposure was simulated based on a previously reported pharmacokinetic model describing the relationship between dietary cadmium intake and urinary cadmium (UCd), as well as a previously published dose‐response relationship between UCd and GFR. Cadmium‐related incidence rate, calculated as the change in the prevalence during a one‐year period, were used to compute the mortality and DALY in all WHO regions. It is estimated that dietary cadmium would result in a median of 12,224 stage 4 and stage 5 new CKD cases per year worldwide, resulting in 2064 global deaths and 70,513 DALYs. These data translate into a median global burden of 1.0 DALY per 100,000 population, which account for 0.2% of the global DALYs of CKD. While these results suggest that the overall impact of dietary cadmium exposure on global CKD is low, they do indicate that reasonable efforts to reduce dietary exposure will result a positive public health impact. This would be particularly the case in areas with elevated levels of dietary cadmium. HighlightsGlobal burden of chronic kidney disease (CKD) from dietary cadmium was estimated.CKD incidence was simulated based on the impact of cadmium on renal function.Disability‐Adjusted Life Years (DALYs) were modeled based on CKD incidence.Dietary cadmium would result in 0.2% of the global CKD burden.

Methods for projecting long-term dietary exposure from short-term survey data for environmental contaminants.

Public health risk assessments often involve dietary exposures over long periods of time. However, most information about dietary consumption habits comes from short-term surveys that are conducted for periods of three days or less. When employed for characterizing long-term exposures, short-term surveys are likely to underestimate the number of persons consuming a particular food, while overestimating the amount consumed by each individual. Direct application of short-term data is particularly misleading for foods that are consumed infrequently. If a more accurate population estimate for chronic dietary intake is needed for a risk assessment, then two general techniques may be considered. The first method is simpler, while the second is more accurate. Both methods require information about the size of the population consuming the food over the long-term period. The simpler fractional adjustment method reduces consumption across the entire distribution by the ratio of consumer population sizes. Since this method will tend to underestimate high-end exposures and overestimate low-end exposures, it is most useful as a quick bounding exercise. Since short-term surveys are better at characterizing the behavior of frequent consumers, a second method employs an exponential function to reduce the low end of the population distribution by a greater amount than the high end. If available, additional information may be used to select the parameter values for the exponential adjustment. Otherwise, an uncertainty range may be used for the parameter values. Since the frequency-based method is more complex, it is most valuable when used as part of a chronic exposure simulation. Examples of both methods are given for the estimation of chronic wine consumption.