Extended One-Generation Reproductive Toxicity (EOGRT) study of benzoic acid in Sprague Dawley rats.

Benzoic acid (BA) was administered in the diet to male and female Sprague Dawley Crl:CD(SD) rats in an OECD Test Guideline 443 Extended One-Generation Reproductive Toxicity (EOGRT) study to test for effects that may occur as a result of pre- and postnatal exposure. The study included cohorts of F1 offspring to evaluate potential effects of benzoic acid on reproduction, the developing immune system, and the developing neurological system with the inclusion of learning and memory assessments. Benzoic acid was incorporated in the diet at concentrations of 0, 7,500, 11,500, and 15,000 mg/kg diet (ppm). These concentrations were selected based on the results of preliminary studies, and, based on average food consumption, were intended to supply BA doses of approximately 0, 500, 750, and 1000 mg/kg bw/day. To avoid exceeding these target dose levels, the dietary concentrations were adjusted (based on historical control body weight and food consumption data) to maintain the target mg/kg bw/day dose levels during those life periods when food intake per unit of body weight was increased to support milk production by females (gestation and lactation) and rapid pup growth (post-weaning). In the parental (F0) generation, survival, clinical observations, organ weights, pathology, hematology, serum chemistry, urinalysis, and bile acids were unaffected by BA administration. Reproductive parameters were also unaffected by BA administration. In the F1 generation, survival, growth and developmental landmarks, organ weights, pathology, immunotoxicity assessment, and neurotoxicity and neurobehavioral parameters such as auditory startle response, locomotor activity, learning and memory assessments were unaffected by BA administration, as were clinical pathology (hematology, serum chemistry, urinalysis, bile acids and thyroid hormones) and reproductive performance. Similarly, no adverse effects or systemic toxicity were observed in the F2 generation. Overall, the highest dietary concentration (15,000 ppm), providing a dosage of approximately 1000 mg/kg bw/day, was the NOAEL for benzoic acid in this EOGRT study.

Caffeine and cardiovascular health.

This report evaluates the scientific literature on caffeine with respect to potential cardiovascular outcomes, specifically relative risks of total cardiovascular disease (CVD), coronary heart disease (CHD) and acute myocardial infarction (AMI), effects on arrhythmia, heart failure, sudden cardiac arrest, stroke, blood pressure, hypertension, and other biomarkers of effect, including heart rate, cerebral blood flow, cardiac output, plasma homocysteine levels, serum cholesterol levels, electrocardiogram (EKG) parameters, heart rate variability, endothelial/platelet function and plasma/urine catecholamine levels. Caffeine intake has been associated with a range of reversible and transient physiological effects broadly and cardiovascular effects specifically. This report attempts to understand where the delineations exist in caffeine intake and corresponding cardiovascular effects among various subpopulations. The available literature suggests that cardiovascular effects experienced by caffeine consumers at levels up to 600 mg/day are in most cases mild, transient, and reversible, with no lasting adverse effect. The point at which caffeine intake may cause harm to the cardiovascular system is not readily identifiable in part because data on the effects of daily intakes greater than 600 mg is limited. However, the evidence considered within this review suggests that typical moderate caffeine intake is not associated with increased risks of total cardiovascular disease; arrhythmia; heart failure; blood pressure changes among regular coffee drinkers; or hypertension in baseline populations.

Human health risk assessment of chloroxylenol in liquid hand soap and dishwashing soap used by consumers and health-care professionals.

A quantitative human risk assessment of chloroxylenol was conducted for liquid hand and dishwashing soap products used by consumers and health-care workers. The toxicological data for chloroxylenol indicate lack of genotoxicity, no evidence of carcinogenicity, and minimal systemic toxicity. No observed adverse effect levels (NOAEL) were established from chronic toxicity studies, specifically a carcinogenicity study that found no cancer excess (18 mg/kg-day) and studies of developmental and reproductive toxicity (100 mg/kg-day). Exposure to chloroxylenol for adults and children was estimated for two types of rinse-off cleaning products, one liquid hand soap, and two dishwashing products. The identified NOAELs were used together with exposure estimates to derive margin of exposure (MOE) estimates for chloroxylenol (i.e., estimates of exposure over NOAELs). These estimates were designed with conservative assumptions and likely overestimate exposure and risk (i.e., highest frequency, 100% dermal penetration). The resulting MOEs ranged from 178 to over 100, 000, 000 indicating negligibly small potential for harm related to consumer or health-care worker exposure to chloroxylenol in liquid soaps used in dish washing and hand washing.

Neurobehavioral hazard identification and characterization for caffeine.

This report evaluates the scientific literature on caffeine with respect to potential central nervous system (CNS) effects, specifically effects on sleep, anxiety, and aggression/risk-taking. Caffeine has been the subject of more scientific safety studies than any other food ingredient. It is important, therefore, to evaluate new studies in the context of this large existing body of knowledge. The safety of caffeine can best be described in a narrative form, and is not usefully expressed in terms of a "bright line" numerical value like an "acceptable daily intake" (ADI). Caffeine intake has been associated with a range of reversible physiological effects, in a few studies at levels of less than 100 mg in sensitive individuals. It is also clear that many people can tolerate much greater levels - perhaps up to 600-800 mg/day or more - without experiencing such effects. The reasons for this type of variability in response are described in this report. Based on all the available evidence, there is no reason to believe that experiencing such effects from caffeine intake has any significant or lasting effect on health. The point at which caffeine intake may cause harm to the CNS is not readily identifiable, in part because data on the effects of daily intakes greater than 600 mg is limited. Effects of caffeine on risk-taking and aggressive behavior in young people have received considerable publicity, yet are the most difficult to study because of ethical concerns and limitations in the ability to design appropriate studies. At present, the weight of available evidence does not support these concerns, yet this should not preclude ongoing careful monitoring of the scientific literature.

Formaldehyde exposure and leukemia: critical review and reevaluation of the results from a study that is the focus for evidence of biological plausibility.

A recent study (Zhang et al., 2010) has provided results attributed to aneuploidy in circulating stem cells that has been characterized as providing potential support for proposed mechanisms for formaldehyde to impact bone marrow. A critical review of the study, as well as a reanalysis of the underlying data, was performed and the results of this reanalysis suggested factors other than formaldehyde exposure may have contributed to the effects reported. In addition, although the authors stated in their paper that "all scorable metaphase spreads on each slide were analyzed, and a minimum of 150 cells per subject was scored," this protocol was not followed. In fact, the protocol to evaluate the presence of monosomy 7 or trisomy 8 was followed for three or less samples in exposed workers and six or less samples in non-exposed workers. In addition, the assays used (CFU-GM) do not actually measure the proposed events in primitive cells involved in the development of acute myeloid leukemia. Evaluation of these data indicates that the aneuploidy measured could not have arisen in vivo, but rather arose during in vitro culture. The results of our critical review and reanalysis of the data, in combination with recent toxicological and mechanistic studies, do not support a mechanism for a causal association between formaldehyde exposure and myeloid or lymphoid malignancies.

Chronic inhalation exposure of rats for up to 104 weeks to a non-carbon-based magnetite photocopying toner.

Male and female Han Wistar rats were exposed for 6 h/day, 5 days/week for 13 or 104 weeks (whole body) to a magnetite photocopying toner. The toner contained 45% to 50% magnetite, with 45% to 50% styrene acrylic resin and less than 5% external additives, including hydrophobic amorphous silica and proprietary surface functional modifiers. Exposure levels were 1, 5, and 25 mg/m(3) for the 13-week study and 1, 4, and 16 mg/m(3) for the 104-week study. Lung toner burdens averaged 36, 288, and 604 microg per lung after 104 weeks' exposure at 1, 4, and 16 mg/m(3). The lung burdens were lower than have been reported in a similar study with a carbon-based toner. There were no significant effects on weight gain or food consumption in either study, or on clinical pathology parameters examined in the 13-week study. After 104 weeks' exposure at 16 mg/m(3), macroscopic examination revealed dark discoloration of the lungs and associated lymph nodes. Lung weights were significantly elevated by 21% and 14% for male and female rats, respectively. Microscopic findings indicative of a mild inflammatory response were similar in both studies, and included the presence of black-pigmented macrophages in the lungs and tracheobronchial and mediastinal lymph nodes; increased incidences of perivascular/peribronchiolar inflammatory cell infiltration; inflammation of the alveolar ducts (characterized by aggregations of black-pigmented alveolar macrophages and interstitial lymphocytic infiltration); increased cellularity of the bronchiole-associated lymphoid tissue; and a few instances of alveolar ciliated metaplasia. The 104-week study showed no increase in the incidence of pulmonary tumors.