Retrospective analysis of dog study data from food and color additive petitions.

As part of the US FDA CFSAN's efforts to explore alternatives to animal testing, we retrospectively analyzed a sample of food additive (FAP) and color additive petitions (CAP) submitted to the FDA for the utility of dog study data in safety assessment. FAPs and CAPs containing dog studies (161 petitions) were classified as decisive (38%), supportive (27%), supplemental (29%) or undermined (6%) based on the impact the dog study data had on the final safety decision. Petitions classified as decisive were further categorized based on if the dog study data were used to a) address a safety concern (35/61); b) calculate an acceptable daily intake (ADI) (11/61); c) withdraw a petition (4/61); d) the effect was unique to the dog (2/61); or e) unclear (9/61). Of 11 petitions where the dog study was used to set an ADI, 7 contained studies where the points of departure (POD) from the dog studies were within an 8-fold range of the rodent with differences in study design likely contributing to the difference in PODs. Future research should include the development and use of qualified alternative studies to replace the use of animal testing for food and color additive safety assessment while ensuring human safety.

Determining the applicability of threshold of toxicological concern approaches to substances found in foods.

Threshold of Toxicological Concern (TTC) decision-support methods present a pragmatic approach to using data from well-characterized chemicals and protective estimates of exposure in a stepwise fashion to inform decisions regarding low-level exposures to chemicals for which few data exist. It is based on structural and functional categorizations of chemicals derived from decades of animal testing with a wide variety of chemicals. Expertise is required to use the TTC methods, and there are situations in which its use is clearly inappropriate or not currently supported. To facilitate proper use of the TTC, this paper describes issues to be considered by risk managers when faced with the situation of an unexpected substance in food. Case studies are provided to illustrate the implementation of these considerations, demonstrating the steps taken in deciding whether it would be appropriate to apply the TTC approach in each case. By appropriately applying the methods, employing the appropriate scientific expertise, and combining use with the conservative assumptions embedded within the derivation of the thresholds, the TTC can realize its potential to protect public health and to contribute to efficient use of resources in food safety risk management.

Rates of allergic sensitization and irritation to oxybenzone-containing sunscreen products: a quantitative meta-analysis of 64 exaggerated use studies.

BACKGROUND/PURPOSE: Oxybenzone is an active ingredient found in sunscreen products that absorbs a broad spectrum of ultraviolet (UV) light, with absorbance peaking in the UVB region and extending into the UVA region. Although the overall incidence of sensitization and irritation associated with oxybenzone in the general population remains unclear, a few studies have reported on the incidence in specific circumstances. However, the relevance of these studies to the general population is limited, because the sample populations reported in these papers generally have consisted of individuals who sought medical attention for pre-existing skin conditions. Therefore, the reported incidence of allergic reactions to oxybenzone in these studies may be overestimated as related to the general population. The objective of this meta-analysis was to determine the safety of oxybenzone in participants recruited from the general population. METHODS: The data from 64 unpublished exaggerated use human repeat insult patch tests (HRIPT) and photoallergy (PA) studies sponsored by Schering-Plough HealthCare Products Inc. between 1992 and 2006 were aggregated and analyzed to evaluate the irritancy and sensitization potential of sunscreen products containing oxybenzone at concentrations between 1% and 6%. RESULTS: Forty-eight of 19 570 possible dermal responses were considered to be suggestive of irritation or sensitization; the mean rate of responses across all formulations was 0.26%. Sensitization rates did not correlate significantly with oxybenzone concentration. The available re-challenge data indicated that only eight of these responses were contact allergies from oxybenzone, and the mean rate of contact allergy to oxybenzone was 0.07%. The source of the skin responses was not confirmed for 15 subjects who were lost to follow-up. However, all subjects were given the opportunity to participate in follow-up testing. CONCLUSION: Our data indicate that sunscreen products formulated with 1-6% oxybenzone do not possess a significant sensitization or irritation potential for the general public. Furthermore, these data suggest that the incidence rate implied in the published literature overestimates the actual incidence of sensitization/irritation due to oxybenzone-containing sunscreen products in the general population.

Chronic toxicity and oncogenicity study with glutaraldehyde dosed in the drinking water of Fischer 344 rats.

Glutaraldehyde (GA) has a wide spectrum of industrial, scientific and biomedical applications. Its potential to produce chronic toxic and/or oncogenic effects was investigated in Fischer 344 rats (100/sex/group) given GA in drinking water for a maximum of 104 weeks. GA concentrations were 0 (control), 50,250 and 1000 ppm, resulting in average daily GA consumptions, respectively, of 0, 4, 17 and 64 mg/kg for males and 0, 6, 25 and 86 mg/kg for females. Interim euthanasia (10/sex/group) was performed at 52 and 78 weeks. Parameters evaluated were clinical signs, body weight, food and water consumption, hematology, serum chemistry, urinalysis, organ weights, gross and microscopic pathology. There were no treatment-related effects on mortality. Absolute body weights and body weight gains of the 250 and 1000 ppm males and females were reduced over the study in a dosage-related manner. Food and water consumption by the 250 and 1000 ppm groups were decreased in a statistically significant dose-related manner over the study, and mean water consumption by the 50 ppm animals was slightly reduced but not with statistical significance. The 250 and 1000 ppm groups had a dose-related decrease in urine volume with increased osmolality, and pH was slightly reduced. Absolute kidney weights were increased in the 250 and 1000 ppm groups at the 52 and 78 week sacrifices, and decreased at 104 weeks. Relative kidney weights were increased at all sacrifice times for the 1000 ppm group, at 52 weeks for the 250 ppm group, and at 72 weeks for the 50 ppm group. The urinalysis and renal weight changes are compatible with a physiological compensatory adaptation to reduced water consumption. Gross and histological evidence for gastric irritation was observed principally in the 1000 ppm rats euthanized at 104 weeks and in animals that died during the study. Bone marrow hyperplasia and renal tubular pigmentation, seen in rats that died and the 104 week euthanasia animals, may have been secondary to a low grade hemolytic anemia in animals with large granular lymphocytic leukemia (LGLL). The only neoplasm that showed a statistically significant increase was LGLL, which occurred at a high incidence in both sexes and all groups, including the controls, for both animals that died and at the 104 week euthanasia. A few instances of LGLL were observed at 78 weeks. The overall incidence of LGLL in the spleen for the 0, 50, 250 and 1000 ppm groups was, respectively, 43, 51, 40 and 46% for males, and 24, 41, 41 and 53% for females. Statistical analyses indicated that the severity of LGLL was associated with the higher dosages of GA in female, but not male, rats. Due to the background and variable incidence of LGLL in the Fischer 344 rat, the finding of a statistical significance only for female rats, and because, there was no clear dose-response relationship, the biological significance of the LGLL findings is unclear. There is the possibility that the significance was a statistical artifact due to the low incidence of LGLL in the female control animals as a result of biological variability within the study. It is also considered to be possible that the chronic dosage of GA in the drinking water resulted in a modification of one or more of the factors responsible for the expression of this common and spontaneously occurring neoplasm in the Fischer 344 rat.