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Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

229

To date, one of the most heavily cited assessments of caffeine safety in the peer-reviewed literature is that issued by Health Canada (Nawrot et al., 2003). Since then, >10,000 papers have been published related to caffeine, including hundreds of reviews on specific human health effects; however, to date, none have compared the wide range of topics evaluated by Nawrot et al. (2003). Thus, as an update to this foundational publication, we conducted a systematic review of data on potential adverse effects of caffeine published from 2001 to June 2015. Subject matter experts and research team participants developed five PECO (population, exposure, comparator, and outcome) questions to address five types of outcomes (acute toxicity, cardiovascular toxicity, bone and calcium effects, behavior, and development and reproduction) in four healthy populations (adults, pregnant women, adolescents, and children) relative to caffeine intake doses determined not to be associated with adverse effects by Health Canada (comparators: 400 mg/day for adults [10 g for lethality], 300 mg/day for pregnant women, and 2.5 mg/kg/day for children and adolescents). The a priori search strategy identified >5000 articles that were screened, with 381 meeting inclusion/exclusion criteria for the five outcomes (pharmacokinetics was addressed contextually, adding 46 more studies). Data were extracted by the research team and rated for risk of bias and indirectness (internal and external validity). Selected no- and low-effect intakes were assessed relative to the population-specific comparator. Conclusions were drawn for the body of evidence for each outcome, as well as endpoints within an outcome, using a weight of evidence approach. When the total body of evidence was evaluated and when study quality, consistency, level of adversity, and magnitude of response were considered, the evidence generally supports that consumption of up to 400 mg caffeine/day in healthy adults is not associated with overt, adverse cardiovascular effects, behavioral effects, reproductive and developmental effects, acute effects, or bone status. Evidence also supports consumption of up to 300 mg caffeine/day in healthy pregnant women as an intake that is generally not associated with adverse reproductive and developmental effects. Limited data were identified for child and adolescent populations; the available evidence suggests that 2.5 mg caffeine/kg body weight/day remains an appropriate recommendation. The results of this systematic review support a shift in caffeine research to focus on characterizing effects in sensitive populations and establishing better quantitative characterization of interindividual variability (e.g., epigenetic trends), subpopulations (e.g., unhealthy populations, individuals with preexisting conditions), conditions (e.g., coexposures), and outcomes (e.g., exacerbation of risk-taking behavior) that could render individuals to be at greater risk relative to healthy adults and healthy pregnant women. This review, being one of the first to apply systematic review methodologies to toxicological assessments, also highlights the need for refined guidance and frameworks unique to the conduct of systematic review in this field.

Concepts: Health care, Medicine, Childbirth, Health, Epidemiology, Reproduction, Nutrition, Caffeine

77

Relatively few studies are available on realistic cumulative risk assessments for dietary pesticide exposure. Despite available studies showing low risk, public concern remains. A method to estimate realistic residue levels based on information from spraying journals and supervised residue trials was described in a previous publication. The present article proposes a new method to estimate average residue levels in imported foods based on residue monitoring data and knowledge about agronomic practices. The two methods were used in combination to estimate average pesticide residue levels in 47 commodities on the Danish market. The chronic consumer exposure was estimated in six Danish diets. The Hazard Index (HI) method was used to assess consumer risk. Despite the conservative (cautious) risk assessment approach, low HI values where obtained. The HI was 16% for adults and 44% for children, combining the risk of all pesticides in the diet.

Concepts: Evaluation, Risk, Assessment, Pesticide, Risk assessment, Soil contamination, Pesticide residue, Pesticides

71

Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormoneindependent breast cancer, MDA-MB231 cells, at 10(-12) to 10(-6) M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and βexpression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study.

Concepts: Gene expression, Cancer, Breast cancer, Human, Menopause, Estrogen, Estrogen receptor, Breast

54

This paper provides guidance on the conduct of new in vivo and in vitro studies on high molecular weight food additives, with carrageenan, the widely used food additive, as a case study. It is important to understand the physical/chemical properties and to verify the identity/purity, molecular weight and homogeneity/stability of the additive in the vehicle for oral delivery. The strong binding of CGN to protein in rodent chow or infant formula results in no gastrointestinal tract exposure to free CGN. It is recommended that doses of high Mw non-caloric, non-nutritive additives not exceed 5% by weight of total solid diet to avoid potential nutritional effects. Addition of some high Mw additives at high concentrations to liquid nutritional supplements increases viscosity and may affect palatability, caloric intake and body weight gain. In in vitro studies, the use of well-characterized, relevant cell types and the appropriate composition of the culture media are necessary for proper conduct and interpretation. CGN is bound to media protein and not freely accessible to cells in vitro. Interpretation of new studies on food additives should consider the interaction of food additives with the vehicle components and the appropriateness of the animal or cell model and dose-response.

Concepts: Protein, Nutrition, In vitro, Flavor, Food processing, Food additive, Food additives, Codex Alimentarius

39

Carrageenan (CGN) is a common food additive used for its gelling and thickening properties. The present study was done to evaluate intestinal permeability, cytotoxicity, and CGN-mediated induction of proinfammatory cytokines. A standard Caco-2 absorption model showed no CGN permeability or cytotoxicity at concentrations of 100, 500, and 1000 μg/mL. In two human intestinal cell lines (HT-29 and HCT-8) CGN (0.1, 1.0, and 10.0 μg/mL) did not induce IL-8, IL-6, or MCP-1 (CCL2) or produce cellular toxicity after 24 h. The TLR4 agonist LPS produced weak induction of IL-8 in HT-29 cells and no induction in HCT-8 cells. The effects of κ-CGN (0.1, 1.0, and 10 μg/mL) on cellular oxidative stress was assessed in HT-29 cells using CM-H2DCFDA as the probe. No effect on oxidative stress was observed after 24 h. In the human (HepG2) liver cell line, ʎ-CGN (0.1, 1.0, 10.0 and 100.0 μg/mL) had no effect on the expression of IL-8, IL-6, or MCP-1 (CCL2) after 24 h. In conclusion, CGN was not absorbed, and was not cytotoxic. It did not induce oxidative stress, and did not induce proinflammatory proteins.

Concepts: DNA, Gene, Cell, Bacteria, Cell biology, Liver, Cellular differentiation, Cytotoxicity

38

Our recent work (Séralini et al., 2012) remains to date the most detailed study involving the life-long consumption of an agricultural genetically modified organism (GMO). This is true especially for NK603 maize for which only a 90-day test for commercial release was previously conducted using the same rat strain (Hammond et al., 2004). It is also the first long term detailed research on mammals exposed to a highly diluted pesticide in its total formulation with adjuvants. This may explain why 75% of our first criticisms arising within a week, among publishing authors, come from plant biologists, some developing patents on GMOs, even if it was a toxicological paper on mammals, and from Monsanto Company who owns both the NK603 GM maize and Roundup herbicide ®. Our study has limits like any one, and here we carefully answer to all criticisms from agencies, consultants and scientists, that were sent to the Editor or to ourselves. At this level, a full debate is biased if the toxicity tests on mammals of NK603 and R obtained by Monsanto Company remain confidential and thus unavailable in an electronic format for the whole scientific community to conduct independent scrutiny of the raw data. In our article, the conclusions of long-term NK603 and Roundup toxicities came from the statistically highly discriminant findings at the biochemical level in treated groups in comparison to controls, because these findings do correspond in an blinded analysis to the pathologies observed in organs, that were in turn linked to the deaths by anatomopathologists. GM NK603 and R cannot be regarded as safe to date.

Concepts: Scientific method, Molecular biology, Genetically modified organism, Genetically modified food, Ice-minus bacteria, Glyphosate, Roundup, Monsanto

36

Glyphosate is the most heavily applied among pesticides in the world, and thus human exposure to this substance continues to increase. WHO changed classification of glyphosate to probably cancerogenic to humans, thus there is urgent need to assess in detail genotoxic mechanism of its action. We have assessed the effect of glyphosate, its formulation (Roundup 360 PLUS) and its main metabolite (aminomethylphosphonic acid, AMPA) in the concentration range from 1 to 1000 μM on DNA damage in human peripheral blood mononuclear cells (PBMCs) incubated. The cells were incubated for 24 h. The compounds studied and formulation induced DNA single and double strand-breaks and caused purines and pyrimidines oxidation. None of compounds examined was capable of creating adducts with DNA, while those substances increased ROS (including •OH) level in PBMCs. Roundup 360 PLUS caused damage to DNA even at 5 μM, while glyphosate and particularly AMPA induced DNA lesions from the concentration of 250 μM and 500 μM, respectively. DNA damage induced by glyphosate and its derivatives increased in order: AMPA, glyphosate, Roundup 360 PLUS. We may conclude that observed changes were not associated with direct interaction of xenobiotics studied with DNA, but the most probably they occurred through ROS-mediated effects.

36

The current paper provides an analysis of the potential number of cancer cases that might be prevented if half the U.S. population increased its fruit and vegetable consumption by one serving each per day. This number is contrasted with an upper-bound estimate of concomitant cancer cases that might be theoretically attributed to the intake of pesticide residues arising from the same additional fruit and vegetable consumption. The cancer prevention estimates were derived using a published meta-analysis of nutritional epidemiology studies. The cancer risks were estimated using U.S. Environmental Protection Agency (EPA) methods, cancer potency estimates from rodent bioassays, and pesticide residue sampling data from the U.S. Department of Agriculture (USDA). The resulting estimates are that approximately 20,000 cancer cases per year could be prevented by increasing fruit and vegetable consumption, while up to 10 cancer cases per year could be caused by the added pesticide consumption. These estimates have significant uncertainties (e.g., potential residual confounding in the fruit and vegetable epidemiologic studies and reliance on rodent bioassays for cancer risk). However, the overwhelming difference between benefit and risk estimates provides confidence that consumers should not be concerned about cancer risks from consuming conventionally-grown fruits and vegetables.

Concepts: Epidemiology, Pesticide, United States Environmental Protection Agency, Fruit, Tomato, Vegetable, Estimation, Vegetarian cuisine

35

The Cold War period is characterized by the infighting between the Western countries and the USSR in diverse areas. One of such fields was development of the weapons of mass destruction. Within various programs on both sides, a wide scale of different agents have been developed. However, information about some of them are still protected under the designation “top secret”. Notwithstanding, in history several cases are known when such information beheld the daylight. One of such cases was the program FOLIANT and NOVICHOK. Both programs were developed by the USSR as a reaction to English/American invention of VX agent. If at least a part of available information is truthful, we can allege that these compounds belong among the most toxic synthetic agents ever. Within this contribution, we have reviewed available Eastern and Western data about the A-agents and their precursors, so-called NOVICHOKs, including their history, synthesis, physical-chemical properties, pharmacological characteristics and clinical manifestation.

31

Over the last two decades, safety concerns about low/no-calorie sweeteners (LNCS) have been described in the archival scientific literature including elevated risk of metabolic syndrome, type 2 diabetes, excessive weight gain, cardiovascular disease, safety, and disruption of the gut microbiome. A recent review by Lobach, Roberts, and Roland in Food and Chemical Toxicology examined 17 research articles on modulation of gut bacteria by LNCS along with other selected publications. In the conclusions of their paper, they claim that LNCS 1) do not affect gut microbiota at use levels and 2) are safe at levels approved by regulatory agencies. Both of these claims are incorrect. The scientific literature on LNCS clearly indicates that it is inappropriate to draw generalized conclusions regarding effects on gut microbiota and safety issues for compounds that vary widely chemical structure and pharmacokinetics. Scientific studies on the sweetener sucralose, used here as a representative LNCS, indicate that this organochlorine compound unequivocally and irrefutably disrupts the gut microbiome at doses relevant to human use. Results of dozens of additional research publications added and reviewed here also raise significant and extensive concerns about the safety of sucralose for the human food supply.