Reassessment of the cadmium toxicological reference value for use in human health assessments of foods.

The U.S. Food and Drug Administration (FDA) developed an oral toxicological reference value (TRV) for characterizing potential health concerns from dietary exposure to cadmium (Cd). The development of the TRV leveraged the FDA's previously published research including (1) a systematic review for adverse health effects associated with oral Cd exposure and (2) a human physiological based pharmacokinetic (PBPK) model adapted from Kjellstrom and Nordberg (1978) for use in reverse dosimetry applied to the U.S. population. Adverse effects of Cd on the bone and kidney are associated with similar points of departure (PODs) of approximately 0.50 µg Cd/g creatinine for females aged 50-60 based on available epidemiologic data. We also used the upper bound estimate of the renal cortical concentration (50 µg/g Cd) occurring in the U.S. population at 50 years of age as a POD. Based on the output from our reverse dosimetry PBPK Model, a range of 0.21-0.36 µg/kg bw/day was developed for the TRV. The animal data used for the animal TRV derivation (0.63-1.8 µg/kg bw/day) confirms biological plausibility for both the bone and kidney endpoints.

A systematic review of adverse health effects associated with oral cadmium exposure.

Scientific data characterizing the adverse health effects associated with dietary cadmium (Cd) exposure were identified in order to make informed decisions about the most appropriate toxicological reference value (TRV) for use in assessing dietary Cd exposure. Several TRVs are available for Cd and regulatory organizations have used epidemiologic studies to derive these reference values; however, risk of bias (RoB) evaluations were not included in the assessments. We performed a systematic review by conducting a thorough literature search (through January 4, 2020). There were 1714 references identified by the search strings and 328 studies identified in regulatory assessments. After applying the specific inclusion and exclusion criteria, 208 studies (Human: 105, Animal: 103) were considered eligible for further review and data extraction. For the epidemiologic and animal studies, the critical effects identified for oral Cd exposure from the eligible studies were a decrease in bone mineral density (BMD) and renal tubular degeneration. A RoB analysis was completed for 49 studies (30 epidemiological and 19 animal) investigating these endpoints. The studies identified through the SR that were considered high quality and low RoB (2 human and 5 animal) can be used to characterize dose-response relationships and inform the derivation of a Cd TRV.

Updated interim reference levels for dietary lead to support FDA's Closer to Zero action plan.

The Centers for Disease Control and Prevention (CDC) utilizes a blood lead reference value (BLRV) to identify children with elevated blood lead levels (BLLs). At or above the BLRV, the CDC recommends actions be taken to reduce children's BLLs. In 2021, the CDC updated its BLRV to 3.5 µg/dL. To align with the CDC's updated BLRV, the FDA is updating its interim reference levels (IRLs) for lead from food to 2.2 µg/day for children and 8.8 µg/day for females of childbearing age. The updated FDA IRLs for lead will serve as a benchmark to evaluate whether lead exposure from food is a potential concern. The children's BLL associated with the updated IRL is less than those predicted by other agencies to result in 1 intelligence quotient point loss. Dietary lead exposure estimates for children in the U.S. suggest exposures greater than the mean may exceed the updated FDA IRL for children, indicating a need for additional efforts to reduce lead in foods consumed by young children. The US FDA is addressing this need by implementing its Closer to Zero action plan to reduce babies' and children's dietary exposure to toxic elements (e.g., lead, cadmium, arsenic, mercury) over time.

A scoping review of infant and children health effects associated with cadmium exposure.

The U.S. FDA initiative, Closer to Zero, identifies actions the agency will take to reduce toxic element exposure from foods eaten by babies and young children with the goal for exposure to be as low as possible. In support of these efforts, this scoping review sought to characterize the available data for primarily dietary cadmium (Cd) exposure and adverse health effects in infants and children. Based on pre-determined inclusion and exclusion criteria, data were extracted from 59 epidemiology studies, and organ systems/anthropometric data supported by > 3 studies were discussed further. For children, most data available were categorized into the nervous (full-scale IQ and attention), cardiovascular (blood pressure) and urinary systems. Studies identified a negative association between urinary Cd and full-scale IQ, though this was dependent on age and sex. More data are needed to support the associations between Cd exposure and adverse nervous system effects. Studies suggested no association between Cd exposure and blood pressure. Data on renal effects in children were too few and diverse to draw conclusions. For infants, anthropometric measurements and birth timing were studied the most. Some studies found a negative relationship between Cd exposure and birthweight, particularly in females. This finding needs further investigation.