Review of evidence relating to occupational exposure limits for alpha-diketones and acetoin, and considerations for deriving an occupational exposure limit for 2,3-pentanedione.

Alpha-diketones, notably diacetyl, have been used as flavoring agents. When airborne in occupational settings, exposures to diacetyl have been associated with serious respiratory disease. Other α-diketones, such as 2,3-pentanedione, and analogues such as acetoin (a reduced form of diacetyl), require evaluation, particularly, in light of recently available toxicological studies. The current work reviewed mechanistic, metabolic, and toxicology data available for α-diketones. Data were most available for diacetyl and 2,3-pentanedione, and a comparative assessment of their pulmonary effects was performed, and an occupational exposure limit (OEL) was proposed for 2,3-pentanedione. Previous OELs were reviewed and an updated literature search was performed. Respiratory system histopathology data from 3-month toxicology studies were evaluated with benchmark dose (BMD) modelling of sensitive endpoints. This demonstrated comparable responses at concentrations up to 100 ppm, with no consistent overall pattern of greater sensitivity to either diacetyl or 2,3-pentanedione. In contrast, based on draft raw data, no adverse respiratory effects were observed in comparable 3-month toxicology studies that evaluated exposure to acetoin at up to 800 ppm (highest tested concentration), indicating that acetoin does not present the same inhalation hazard as diacetyl or 2,3-pentanedione. To derive an OEL for 2,3-pentanedione, BMD modelling was conducted for the most sensitive endpoint from 90-day inhalation toxicity studies, namely, hyperplasia of nasal respiratory epithelium. On the basis of this modelling, an 8-hour time-weighted average OEL of 0.07 ppm is proposed to be protective against respiratory effects that may be associated with chronic workplace exposure to 2,3-pentanedione.

A hard look at FDA's review of GRAS notices.

Generally Recognized as Safe (GRAS) substances are exempt from premarket approval; however, the standard of "reasonable certainty of no harm" is the same. In 1997, the voluntary GRAS affirmation process was replaced with the voluntary U.S. Food and Drug Administration (FDA) GRAS notice process. Under the GRAS notice process, pivotal safety data are required to be in the public domain, and consensus of safety among experts is required. FDA issues responses of "FDA has no questions", "Notice does not provide a basis for a GRAS determination", or, "At Notifier's request, FDA ceased to evaluate the notice." Of 528 notices reviewed, there were 393 "no questions letters", 17 "insufficient basis letters", and 84 "cease to evaluate letters". Of those deemed to be insufficient, most failed to meet the general recognition criteria. Only four raised questions about potential safety, of which three received a no questions letter upon providing more data. Of the 84 withdrawn notices, 22 received a no questions letter upon resubmission. In spite of criticisms, the FDA GRAS notice process is clearly defined, efficient, and cost-effective, and there have been no known public health issues following its implementation.

Proof of concept for a banding scheme to support risk assessments related to multi-product biologics manufacturing.

A banding scheme theory has been proposed to assess the potency/toxicity of biologics and assist with decisions regarding the introduction of new biologic products into existing manufacturing facilities. The current work was conducted to provide a practical example of how this scheme could be applied. Information was identified for representatives from the following four proposed bands: Band A (lethal toxins); Band B (toxins and apoptosis signals); Band C (cytokines and growth factors); and Band D (antibodies, antibody fragments, scaffold molecules, and insulins). The potency/toxicity of the representative substances was confirmed as follows: Band A, low nanogram quantities exert lethal effects; Band B, repeated administration of microgram quantities is tolerated in humans; Band C, endogenous substances and recombinant versions administered to patients in low (interferons), intermediate (growth factors), and high (interleukins) microgram doses, often on a chronic basis; and Band D, endogenous substances present or produced in the body in milligram quantities per day (insulin, collagen) or protein therapeutics administered in milligram quantities per dose (mAbs). This work confirms that substances in Bands A, B, C, and D represent very high, high, medium, and low concern with regard to risk of cross-contamination in manufacturing facilities, thus supporting the proposed banding scheme.

A reassessment of risk associated with dietary intake of ochratoxin A based on a lifetime exposure model.

Mycotoxins, such as ochratoxin A (OTA), can occur from fungal growth on foods. OTA is considered a possible risk factor for adverse renal effects in humans based on renal tumors in male rats. For risk mitigation, Health Canada proposed maximum limits (MLs) for OTA based largely on a comparative risk assessment conducted by Health Canada (Kuiper-Goodman et al., 2010), in which analytical data of OTA in foods were used to determine the possible impact adopting MLs may have on OTA risks. The EU MLs were used for comparison and resultant risk was determined based on age-sex strata groups. These data were reevaluated here to determine comparative risk on a lifetime basis instead of age strata. Also, as there is scientific disagreement over the mechanism of OTA-induced renal tumors, mechanistic data were revisited. On a lifetime basis, risks associated with dietary exposure were found to be negligible, even without MLs, with dietary exposures to OTA three to four orders of magnitude below the pivotal animal LOAEL and the TD(05). Our review of the mechanistic data supported a threshold-based mechanism as the most plausible. In particular, OTA was negative in genotoxicity assays with the highest specificity and levels of DNA adducts were very low and not typical of genotoxic carcinogens. In conclusion, OTA exposures from Canadian foods do not present a significant cancer risk.

Lack of human tissue-specific correlations for rodent pancreatic and colorectal carcinogens.

To better understand the relationships between chemical exposures and human cancer causation, incidence data for human cancer types were identified and pancreatic and colorectal cancers were studied in-depth to assess whether data supporting the causation of pancreatic or colorectal tumors by chemicals in rodents is predictive of causation by the same chemicals of the same tumors in humans. A search of the Carcinogenic Potency Database, the National Toxicology Program (NTP) technical report database, and the published literature identified 38 and 39 chemicals reported to cause pancreatic and colorectal tumors, respectively, in mice or rats. For each of these chemicals, searches were conducted of the International Agency for Research on Cancer monographs, the NTP Report on Carcinogens, and the published literature for evidence of induction of the same tumors in humans. Based on this evaluation, no conclusive evidence was identified to suggest that chemicals reported to cause pancreatic or colorectal tumors in rodents also cause these tumors in humans. These findings suggest that pancreatic tumor data from mouse and rat bioassays are of limited utility with regard to predicting similar tumor induction in humans. For colorectal cancer, a lack of correlation was noted for the vast majority of chemicals.

Technological challenges of addressing new and more complex migrating products from novel food packaging materials.

The risk assessment of migration products resulting from packaging material has and continues to pose a difficult challenge. In most jurisdictions, there are regulatory requirements for the approval or notification of food contact substances that will be used in packaging. These processes generally require risk assessment to ensure safety concerns are addressed. The science of assessing food contact materials was instrumental in the development of the concept of Threshold of Regulation and the Threshold of Toxicological Concern procedures. While the risk assessment process is in place, the technology of food packaging continues to evolve to include new initiatives, such as the inclusion of antimicrobial substances or enzyme systems to prevent spoilage, use of plastic packaging intended to remain on foods as they are being cooked, to the introduction of more rigid, stable and reusable materials, and active packaging to extend the shelf-life of food. Each new technology brings with it the potential for exposure to new and possibly novel substances as a result of migration, interaction with other chemical packaging components, or, in the case of plastics now used in direct cooking of products, degradation products formed during heating. Furthermore, the presence of trace levels of certain chemicals from packaging that were once accepted as being of low risk based on traditional toxicology studies are being challenged on the basis of reports of adverse effects, particularly with respect to endocrine disruption, alleged to occur at very low doses. A recent example is the case of bisphenol A. The way forward to assess new packaging technologies and reports of very low dose effects in non-standard studies of food contact substances is likely to remain controversial. However, the risk assessment paradigm is sufficiently robust and flexible to be adapted to meet these challenges. The use of the Threshold of Regulation and the Threshold of Toxicological Concern concepts may play a critical role in the risk assessment of new food packaging technologies in the future.

An evaluation of the possible carcinogenicity of bisphenol A to humans.

Bisphenol A (BPA) is a monomer component of polycarbonate plastics and epoxy resins. These resins are used in numerous consumer products, including food-contact plastics. There has been considerable scientific debate about the relevance to humans of reported estrogenic actions of BPA. Much less attention has been focused on the carcinogenic potential of BPA. The carcinogenic potential of BPA was assessed through a review of metabolic data, genetic toxicity studies, long-term toxicity/carcinogenicity studies, and estimates of consumer exposure. Following a weight-of-evidence approach as recommended by IARC and U.S. EPA, it was concluded that BPA is not likely to be carcinogenic to humans. The bases for this conclusion included: (a) the results of an NTP study which provided no substantive evidence to indicate that BPA is carcinogenic to rodents; (b) the lack of activity of BPA, at noncytotoxic concentrations, in standard in vitro genetic toxicity tests; (c) the lack of genotoxic activity of BPA in a GLP-compliant in vivo mouse micronucleus assay; and (d) the results of metabolism studies showing BPA is rapidly glucuronidated without evidence of formation of potentially reactive intermediates, except possibly at high doses that could saturate detoxication pathways. In addition, exposure assessment reveals that current use of BPA would result in only a trivial human exposure.