Lois A. Haighton

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 (), 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 TD05. 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.

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.

Safety assessment and risk–benefit analysis of the use of azodicarbonamide in baby food jar closure technology: Putting trace levels of semicarbazide exposure into perspective – A review

The discovery of trace levels of semicarbazide (SEM) in bottled foods (especially baby foods) led to a consideration of the safety of this hydrazine compound by regulatory agencies worldwide. Azodicarbonamide, which is used in the jar-sealing technology known as Press On-Twist Off (or Push-Twist/PT) closures for the formation of a hermetic, plastisol seal, partially degrades with the heat of processing to form trace amounts of SEM. This review has evaluated the potential toxicological risks of resulting exposure to SEM and also the benefit of the PT technology (with azodicarbonamide) in the context of possible microbial contamination. It also considers the potential impact on infant nutrition if parents come to the conclusion that commercial baby foods are unsafe. SEM shows limited genotoxicity in vitro that is largely prevented by the presence of mammalian metabolic enzymes. Negative results were found in vivo in DNA alkaline elution, unscheduled DNA synthesis and micronucleus assays. This pattern is in contrast to the genotoxic hydrazines that also have been shown to cause tumours. Carcinogenicity studies of SEM are of limited quality, show a questionable weak effect in mice at high doses, which are not relevant to human exposure at trace levels, and show no effect in the rat. The IARC has assigned SEM as Group 3, ‘Not classifiable as to its carcinogenicity to humans’. Based on estimates of exposure to infants consuming baby foods (with the assumption of SEM levels at the 95th percentile of 20 ng g−1 in all of the consumed ‘ready-to-eat’ foods) compared with a no observed adverse effect level (NOAEL) in developmental toxicity studies, the margin of safety is more than 21 000. Since the risk of an adverse effect is negligible, it is clear that any theoretical risk is outweighed by the benefits of continuing use of the PT closure (with azodicarbonamide blowing agent) to ensure both the microbial integrity and availability of commercial baby foods as a valuable source of infant nutrition.

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.

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.

Bisphenol A and infant neonatal neurobehavior.

We read with interest the article “Case Report: High Prenatal Bisphenol A Exposure and Infant Neonatal Neurobehavior” by Sathyanarayana et al. (2011). In their article, the authors proposed a potential association between a single, exceedingly high concentration of urinary bisphenol A (BPA) measured at the beginning of the third trimester of pregnancy in a single case mother and a single abnormal neurological assessment conducted 4 months later in a single and apparently otherwise healthy infant at approximately 1 month of age. We have several comments and concerns about this article and its conclusions. First, the urinary BPA results for the mother at the 16-week gestation test and just after birth were not abnormally elevated; the only elevated concentration was at the 26-week gestation test. Sathyanarayana et al. (2011) reported that the elevated BPA level was the highest of any reported in the peer-reviewed literature and that the bioanalytical laboratory repeated the analysis to confirm the result. The actual values detected in the repeated analysis were not provided in the article, precluding readers from independently concluding that the result was likely not spurious. Second, Sathyanarayana et al. (2011) stated that at 26 weeks of gestation the majority of the BPA in the urine sample was conjugated, indicating that it had been metabolized and thus did not reflect external contamination. It should be noted that glucuronidated BPA is not biologically active. The authors did not propose a potential mechanism by which conjugated BPA may exert neurological effects. Third, although the neurological assessment conducted on the infant at approximately 1 month of age was considered abnormal, neurological assessments at 14 hr after birth and annually at 1–5 years of age were within normal limits, suggesting a spurious event. Also, it is unclear whether “normal limits” refers to results at 1–5 years of age for children in the Health Outcomes and Measures of the Environment (HOME) Study from which this case study was generated (and with which the 1-month assessment results were compared) or to some other data set. If it is the latter, the authors would appear to have compared the child’s assessment results with two different data sets and drawn different conclusions from them without indicating whether (and how) the data sets differ. The preceding items and other statements in the article raise doubt about the plausibility of a link between the single high urinary BPA measurement and the single abnormal neurological assessment. For example, Sathyanarayana et al. (2011) did not know how long the child exhibited symptoms after the abnormal assessment was conducted. The authors did not indicate that any follow-up tests were performed to detect ailments that may have been the cause of the abnormal findings; they stated only that there was “no obvious etiology.” The authors reported that they referred the mother to her primary physician, but the only information they provided regarding the results of the follow-up or when it occurred was that [The] abnormal findings were not noted by any other medical assessments performed by health care providers, including the primary medical doctor for the infant. (Sathyanarayana et al. 2011) Most strikingly, the authors stated that Other infants within the HOME Study had abnormal neurologic examinations, but some of these mothers did not have elevated prenatal urinary BPA concentrations. These cases may have resulted from other etiologies of abnormal neurobehavior that have not yet been explored. We argue that the case infant also may have had such etiologies that were not explored. Thus, it is unclear to us why Sathyanarayana et al. (2011) chose to conduct and report a case study on this single infant, other than the fact that the mother had an unusually high urinary BPA concentration at a single time point. In conclusion, we feel that it is highly likely that the elevated third-trimester urinary BPA concentration had absolutely nothing to do with the single abnormal neurological assessment in the case infant. We do not consider this study to be “hypothesis generating” but rather to simply fan the flames of a topic that has received substantial media attention, much of which is overblown and not supported scientifically. We recommend that the authors consider reviewing the Bradford Hill criteria for establishing causality before suggesting and publishing possible cause-and-effect relationships based on a single case study.

Systematic review and evaluation of aspartame carcinogenicity bioassays using quality criteria

Abstract The current review assessed cancer studies of aspartame based on a quality appraisal using the Klimisch grading system. Nine studies having complete histopathology were included: three 2‐year studies by Searle; three transgenic mice studies by the NTP; three lifetime studies by the Ramazzini Institute. A tenth study limited to brain tumors was not rated. None were determined as Klimisch Code 1 (reliable without restrictions). The Searle studies predated GLP standards but their methodology was comparable; transgenic mouse models are not validated, but are accepted as supporting data. These studies were rated Klimisch Code 2 (reliable with restrictions). The Ramazzini Institute used a lifetime model of their own design that has been questioned due to high rates of spontaneous tumors, issues with tumor type diagnosis and concerns about the impact of chronic infections. As many of these problems could be attributed to using animals that died or were terminated near end of life, along with the other problems noted, these studies were rated Klimisch Code 3 (not reliable). As the Klimisch Code 2 studies demonstrated a lack of carcinogenic potential, and as aspartame is hydrolyzed to common components and lacks genotoxic activity, a conclusion that aspartame is not carcinogenic is supported. HighlightsAspartame cancer bioassay methods evaluated using quality criteria.Pivotal studies evaluated against the Klimisch grading system.Studies with highest rating support that aspartame is not carcinogenic in rodents.