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Scientists participating in 2 multistakeholder meetings in 2011 and in other events have identified a number of ways in which the methods the U.S. Food and Drug Administration (FDA) uses to assess the safety of chemicals in human food should be improved and updated. We evaluated whether FDA's current methods, including its decision-making process, are outdated, as alleged by its critics. We examined a 1982 report by the Select Committee on GRAS Substances (SCOGS) that included suggestions to enhance food additive safety. FDA established SCOGS to review the safety of "generally recognized as safe" (GRAS) substances in response to a directive by President Nixon. When evaluating FDA's response to SCOGS' suggestions, we found that many remain unresolved and relevant today. Our analysis demonstrates that in many cases FDA has not kept pace with scientific developments. Although difficult to pinpoint, we concluded that this situation became more significant after 1997, when FDA launched the voluntary GRAS notification program aimed at enticing manufacturers to inform the agency of their own safety decisions. Looking forward, we recommend that the agency convene an unbiased and independent expert workgroup to conduct a comprehensive review of FDA's science and decision making and develop a path to modernize food additives safety assessment. Areas of concern include toxicology test guidelines, tools used to predict health outcomes, conflict of interest in manufacturers' decisions, lack of a reassessment strategy, and lack of a definition of harm.

Food additives and substances considered “generally recognized as safe” must not be allowed in food unless there is a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use. Scientists determine safety by ensuring that the expected exposure is less than the acceptable daily intake. The U.S. Food and Drug Administration (FDA) provides guidance documents to assist safety assessors in this analysis. A November 2011 workshop sponsored by The Pew Charitable Trusts, the Institute of Food Technologists, and the journal Nature reviewed the agency's exposure assessment approaches. More than 70 experts from government (including FDA), industry, academia, and public interest organizations examined the principles underlying dietary exposure assessments for substances added to human food, and responded to questions about current methods. FDA's approach was seen as serving the agency reasonably well, but participants identified opportunities for improvement. Although reaching a consensus was not a goal, general agreements emerged that FDA should develop a science-based framework to prioritize and reassess prior safety decisions, and conduct more extensive postmarket monitoring. Participants discussed the possibility of harmonizing different approaches to assess dietary exposure. They generally agreed that collaboration, communication, and exchanging scientific information between agencies and stakeholders would help assessors use the most current information to make better decisions. Participants identified data gaps and opportunities to fill the gaps using new tools and technologies. Participants generally agreed on the need to consider all dietary sources in a cumulative dietary exposure assessment.

Science and expert judgment are the foundation for safety assessments of chemicals added to food to ensure their use is safe. Hazard characterization is the first step in a safety assessment. Advances in science and technology pose challenges to the regulatory system and raise questions about whether the current hazard identification and characterization process is able to systematically and transparently encompass such advances while remaining defensible. An April 2011 workshop sponsored by The Pew Charitable Trusts, the Institute of Food Technologists, and the journal Nature brought together over 80 experts in science and food policy from government, industry, academia, and public interest organizations to examine the principles underlying the development and use of scientific evidence needed for chemical hazard characterization. Participants discussed challenges of identifying adverse health effects, advances in science, uses of new screening technologies and human biomonitoring data, updating of study designs, and development and review of toxicity test guidelines. Brainstorming sessions allowed participants to propose alternatives to enhance FDA's evaluation of science for safety assessment. Although there was no intention to reach a consensus, several themes emerged including the need for clear procedures to develop validated toxicity tests; importance of regularly updating guidance documents relied upon by regulators and industry; benefits of transparency and public access to information; potential for greater interagency collaboration; opportunities to improve hypothesis-based research to make it more useful to regulatory decision making; and importance of staying abreast of scientific developments to ensure that safety assessments are made using sensitive and relevant methods.

The Food Additives Amendment of 1958 is the foundation for the U.S. food additive regulatory program, which oversees most substances added to food. This article is a comprehensive review of the program, including original analysis of pre- and postmarket safety standards for various categories and subcategories of substances and their uses; assigning the more than 10000 substances currently allowed in human food to those categories; and analyzing the U.S. Food and Drug Administration's (FDA) review of more than 1900 petitions and notifications received from 1990 to 2010. Overall, federal agencies made approximately 40% of the 6000 safety decisions allowing substances in human food. These decisions allowed an estimated 66% of the substances currently believed to be used in food. Manufacturers and a trade association made the remaining decisions without FDA review by concluding that the substances were generally recognized as safe (GRAS). Robust premarket safety decisions are critical since FDA has limited resources to monitor potentially significant scientific developments and changing uses of a substance after it enters commerce and only has access to published data or data submitted to it. In the late 1990s, FDA moved from promulgating rules for its decisions for food contact and GRAS substances to reviewing manufacturer safety decisions and posting the results of the review on the agency's website. This shift appears to have encouraged manufacturers to submit their decisions to FDA for review but has limited public opportunity to provide input.

The hypothesis that prenatal exposure to endocrine disruptors might cause cancer arose from challenging two well-accepted notions: (i) mammalian development is merely the unfolding of a genetic programme and (ii) only mutagenic agents can cause cancer. This hypothesis required challenging genetic determinism. The ecological developmental biology (eco-devo) movement revitalized the concept of developmental plasticity through the occurrence of polyphenisms (a single genotype produces diverse phenotypes which are determined by environmental cues). Based on the principles of eco-devo and the tissue organization field theory of carcinogenesis and neoplasia, we tested the hypothesis that exposure to xenoestrogens during foetal development in rats increased the propensity to develop mammary cancer during adulthood. We chose exposure to bisphenol A (BPA) as a model for environmental oestrogen exposure. This endocrine disruptor induced the development of ductal hyperplasias and carcinoma in situ. These highly proliferative lesions contained an increased number of oestrogen receptor alpha-positive cells. Thus, foetal BPA exposure was sufficient to induce the development of oestrogen-sensitive pre-neoplastic and neoplastic lesions in the mammary gland in the absence of any additional treatment aimed at increasing tumour incidence.

Perturbations in the foetal environment predispose individuals to diseases that become apparent in adulthood. These findings prompted researchers to hypothesize that foetal exposure to environmental oestrogens may play a role in the increased incidence of breast cancer observed in European and US populations over the last 50 years. There is widespread human exposure to bisphenol A, an oestrogenic compound that leaches from dental materials and consumer products. In CD-1 mice, perinatal exposure to environmentally relevant bisphenol A levels induced alterations of the mammary gland architecture. Bisphenol A increased the number of terminal end buds at puberty and terminal ends at 6 months of age and increased ductal lateral branching at 4 months of age. Exposed mice also showed an enhanced sensitivity to oestradiol when ovariectomized prior to puberty. All these parameters are associated in human beings with an increased risk for developing breast cancer. To assess whether bisphenol A induces mammary gland neoplasia, we chose a rat model because it more closely mimics the human disease than mouse models. Examination of the mammary glands of Wistar/Furth rats during early adulthood revealed that gestational exposure to bisphenol A induced the development of pre-neoplastic lesions and carcinoma in situ in the absence of any additional treatment aimed at increasing tumour development. Emerging epidemiological data reveal an increased incidence of breast cancer in women exposed to diethylstilboestrol during gestation. Hence, both animal experiments and epidemiological data strengthen the hypothesis that foetal exposure to xenooestrogens may be an underlying cause of the increased incidence of breast cancer observed over the last 50 years.

Summary Sheep uterine cervices and cervical mucus were heavily infiltrated by neutrophils during labour, whereas samples of cervices obtained from non-pregnant controls had no infiltrate. The neutrophilic infiltrate of the sheep uterine cervix at term was not homogeneously distributed throughout the organ: luminal mucus contained more neutrophils than tissues which, in turn, displayed a differential distribution, the superficial subepithelial layer being more heavily infiltrated than the deeper submucous layers. A widespread collagenolysis was observed in the sheep uterine cervix at term. The homogeneous morphological aspect of degradation of collagen fibres throughout the whole cervical stroma contrasted with the above-mentioned differential distribution of neutrophils. On the basis of previous reports showing that collagenolysis follows the leukocytic invasion of human and rat cervices at term, a possible role for the neutrophilic infiltrate of the sheep uterine cervix is discussed.