Lead chromate pigment in the form of the commercial pigment, Pigment Yellow 34, CAS No. 1344-37-2, used in the plastics and coatings industries, did not induce chromosome aberrations in Chinese hamster ovary (CHO) cell line WB(L). Lead chromate pigment is essentially insoluble in water, and in an effort to test the material under realistic conditions, no attempt to solubilize the pigment was made. These results are significant because others have reported lead chromate to cause genotoxicity in various assays, but only under conditions in which its aqueous solubility was artificially enhanced.

Abstract LI12542F6, a botanical extract composed of Sphaeranthus indicus and Mangifera indica, was evaluated for mutagenicity in bacteria, clastogenicity in mouse bone marrow, acute oral and dermal toxicity in the rat, irritation (dermal, eye) in rabbit, and subacute and subchronic toxicity (28 and 90 days) in the rat. All studies followed standard OECD test protocols, in accordance with the principles of Good Laboratory Practice (GLP). LI12542F6 did not induce mutations in the bacterial assay using Salmonella and Escherichia coli strains, nor did it induce genotoxic effects in erythrocytes from mouse bone marrow. LI12542F6 was found to have oral and dermal LD50 values greater than the limit dose of 2,000 mg/kg body weight in the rat. In an eye irritation/corrosion test, LI12542F6 caused conjunctival redness, corneal opacity, and chemosis and is classified as Category 2A (“irritating to eyes – reversible eye effect”). Doses in the 28‐day and 90‐day rat oral toxicity studies were 0, 500, 1,000, and 1,500 and 0, 1,000, 1,500, and 2,000 mg/kg body weight/day, respectively, administered by gavage. Both studies featured a recovery period. Minor effects were random and not treatment related except for local irritation of the forestomach in the 28‐day study, evidenced by histopathologic examination, in mid‐ and high‐dose animals. The frequency and severity of these effects were reduced in the recovery group; irritation was not found in the forestomach of rats in the 90‐day study. The no observed adverse effect level (NOAEL) was greater than the highest dose tested, that is, >2,000 mg/kg in the 90‐day study. This botanical composition will be marketed commercially for muscle health as Myotor™.

Sucralose is a non-caloric high intensity sweetener that is approved globally for use in foods and beverages. This review provides an updated summary of the literature addressing the safety of use of sucralose. Studies reviewed include chemical characterization and stability, toxicokinetics in animals and humans, assessment of genotoxicity, and animal and human feeding studies. Endpoints evaluated include effects on growth, development, reproduction, neurotoxicity, immunotoxicity, carcinogenicity and overall health status. Human clinical studies investigated potential effects of repeated consumption in individuals with diabetes. Recent studies on the safety of sucralose focused on carcinogenic potential and the effect of sucralose on the gut microflora are reviewed. Following the discovery of sweet taste receptors in the gut and studies investigating the activation of these receptors by sucralose lead to numerous human clinical studies assessing the effect of sucralose on overall glycemic control. Estimated daily intakes of sucralose in different population subgroups, including recent studies on children with special dietary needs, consistently find that the intakes of sucralose in all members of the population remain well below the acceptable daily intake. Collectively, critical review of the extensive database of research demonstrates that sucralose is safe for its intended use as a non-caloric sugar alternative.

Abstract Palmitoylethanolamide (PEA) is a natural fatty acid amide found in a variety of foods, which was initially identified in egg yolk. MicroPEA of defined particle size (0.5–10 μm) was evaluated for mutagenicity in Salmonella typhimurium, for clastogenicity/aneuploidy in cultured human lymphocytes, and for acute and subchronic rodent toxicity in the rat, following standard OECD test protocols, in accordance with Good Laboratory Practice (GLP). PEA did not induce mutations in the bacterial assay using strains TA1535, TA97a, TA98, TA100, and TA102, with or without metabolic activation, in either the plate incorporation or liquid preincubation methods. Similarly, PEA did not induce genotoxic effects in human cells treated for 3 or 24 h without metabolic activation, or for 3 h with metabolic activation. PEA was found to have an LD50 greater than the limit dose of 2000 mg/kg body weight (bw), using the OECD Acute Oral Up and Down Procedure. Doses for the 90‐day rat oral toxicity study were based on results from the preliminary 14‐day study, that is, 250, 500, and 1000 mg/kg bw/day. The No Effect Level (NOEL) in both subchronic studies was the highest dose tested.

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 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.

The threshold of toxicological concern (TTC) concept proposes that an exposure threshold value can be derived for chemicals, below which no significant risk to human health or the environment is expected. This concept goes further than setting acceptable exposure levels for individual chemicals, because it attempts to set a de minimis value for chemicals, including those of unknown toxicity, by taking the chemical's structure or mode of action (MOA) into consideration. This study examines the use of the TTC concern concept for endocrine active substances (EAS) with an estrogenic MOA. A case study formed the basis for a workshop of regulatory, industry and academic scientists held to discuss the use of the TTC in aquatic environmental risk assessment. The feasibility and acceptability, general advantages and disadvantages, and the specific issues that need to be considered when applying the TTC concept for EAS in risk assessment were addressed. Issues surrounding the statistical approaches used to derive TTCs were also discussed. This study presents discussion points and consensus findings of the workshop. Integr Environ Assess Manag 2010; 6:2–11. © 2009 SETAC

Because of their unique physicochemical properties, engineered nanoparticles have the potential to significantly impact respiratory research and medicine by means of improving imaging capability and drug delivery, among other applications. These same properties, however, present potential safety concerns, and there is accumulating evidence to suggest that nanoparticles may exert adverse effects on pulmonary structure and function. The respiratory system is susceptible to injury resulting from inhalation of gases, aerosols, and particles, and also from systemic delivery of drugs, chemicals, and other compounds to the lungs via direct cardiac output to the pulmonary arteries. As such, it is a prime target for the possible toxic effects of engineered nanoparticles. The purpose of this article is to provide an overview of the potential usefulness of nanoparticles and nanotechnology in respiratory research and medicine and to highlight important issues and recent data pertaining to nanoparticle-related pulmonary toxicity.

The popularity of traditional or alternative medicines is evidenced by the volume of such products available around the world. In Canada, the Natural Health Product Regulations, promulgated in 2004, categorized such products as natural health products and outlined requirements for their premarket assessment of safety, efficacy and quality. With a new regulatory framework for over 40 000 products on the Canadian market, the Natural Health Products Directorate (NHPD) has faced numerous challenges in its goal to license all products. As such, the policies and practices of the NHPD and other related regulatory agencies within Health Canada are constantly changing in order to address these issues. The basic principles of the Regulations and examples of major issues faced by the NHPD are discussed.

Because of their unique physicochemical properties, engineered nanoparticles have the potential to significantly impact respiratory research and medicine by means of improving imaging capability and drug delivery, among other applications. These same properties, however, present potential safety concerns, and there is accumulating evidence to suggest that nanoparticles may exert adverse effects on pulmonary structure and function. The respiratory system is susceptible to injury resulting from inhalation of gases, aerosols, and particles, and also from systemic delivery of drugs, chemicals, and other compounds to the lungs via direct cardiac output to the pulmonary arteries. As such, it is a prime target for the possible toxic effects of engineered nanoparticles. The purpose of this article is to provide an overview of the potential usefulness of nanoparticles and nanotechnology in respiratory research and medicine and to highlight important issues and recent data pertaining to nanoparticle-related pulmonary toxicity.

There exists the possibility that non-target livestock may receive trace exposure to medications in feed due to residue carryover from previous production runs of medicated feeds at feed mills. We have developed a method by which ADI-Derived Drug Carryover Levels (ADCLs) can be established. It is a practical approach compared to the “zero” levels of residue carryover that may be expected or required by regulatory authorities. The methodology involves application of various safety/uncertainty factors to concentrations of active ingredients (a.i.) already approved for use in medicated feeds for target species. The starting point for each a.i., to be consistent, and to represent the highest possible carryover, is the highest approved concentration for any target animal species, recognizing that this is an approved level based on established ADI and agency review of supporting safety data specific to each a.i. (Hence, these guidance values are characterized to be ‘ADI-derived’.) Safety factors are then applied to account for: (a) interspecies extrapolation, (b) differences in the body weights of target and non-target species (i.e., smaller animals receive higher exposures on a body weight basis for a given dietary concentration), (c) a.i. with clear contraindications for use in certain non-target species (i.e., a priori knowledge of non-target species sensitivity), and (d) withdrawal times (i.e., for a.i. that require a washout period prior to slaughter there is potential exposure to non-target species through other feeds not requiring a washout period). The values of the safety/uncertainty factors range from 1 to 3, 1 to 3.17, 1 to 10, and 1 to 10, for each of conditions (a), (b), (c), and (d), respectively. The “proposed safety factor” to apply to the approved concentration in medicated feed is calculated as the product of the values for each of (a) through (d). The final safety factor is the greater of the proposed safety factor or a default minimum safety factor of 30. ADCLs were calculated for several a.i. and compared to limits of quantitation available for detection of carryover residues in animal feeds. This methodology may be used in its present or modified form in any jurisdiction in which mediated feeds are approved. As a start, this approach has been applied to several example products approved and in use in Canada.

In the comment(quant-ph/0103003) Eggeling,Vollbrecht and Wolf suspect our method in quant-ph/0102133 is not practical. Here we explain our result and method and show that our example can tell one how to judge a separable state, and so our method is practical, at least for many mixed states.

The subchronic toxicity of antimony in drinking water was studied in the rat. Male and female Sprague-Dawley rats (127–135 g body weight, 15 animals per group) were exposed to a soluble trivalent antimony salt, potassium antimony tartrate, in drinking water at concentrations of 0.5, 5, 50 and 500 ppm for 13 wk. Control rats received tap water as drinking water. An additional 10 male and 10 female rats were included in each of the control and 500 ppm groups and were given tap water for a further 4-wk recovery period after the 13-week treatment period. During treatment, the highest dose animals of both sexes consumed significantly less water and showed suppressed body weight gain. During recovery, water intake was quickly restored to that of the control groups and body weight gain was accelerated. At termination, one highest dose male had a cirrhotic liver, and three highest dose males exhibited gross haematuria. Female rats showed a dose-related decrease in serum glucose starting at 5 ppm, and rats of both sexes in the highest dose group had slightly decreased alkaline phosphatase activity and creatinine. The highest dose males had decreased red blood cell and platelet counts and increased mean corpuscular volume. Hepatic glutathione S-transferase activity was increased in the highest dose males and females and ethoxyresorufin-O-deethylase activity was increased in the highest dose males. In the highest dose groups, mild adaptive histological changes were observed in the thyroid, liver and pituitary gland of both sexes, and in the spleen of male rats and thymus of female rats. After a 4-wk recovery period, the pituitary gland of both sexes appeared normal and the changes in the liver and thyroid of both sexes became less severe. On the other hand, minimal changes persisted in the spleen of both sexes and in the thymus of males. Tissue antimony levels were dose-related and follow the order: red blood cells > > spleen, liver > kidney > brain, fat > serum. After the recovery period, antimony level in the highest dose animals decreased for all tissues except the spleen, which remained the same as before recovery. A NOAEL of 0.5 ppm antimony in drinking water, equivalent to an average intake of 0.06 mg/kg body weight/day, was established on the basis of the histological and biochemical changes observed at 5.0 ppm.

Since its development by Dr. Bruce Ames and his coworkers, the Salmonella typhimurium/mammalian microsome mutagenicity assay has been used widely throughout the world. Many authors have suggested various modifications and made recommendations in regards to this assay. Although the recommendations of a panel of experts was published in 1979 by de Serres and Shelby, a committee of members of the Environmental Mutagen Society (EMS) initiated this effort in response to the encouragement by the American Society of Testing and Materials (Committee E47.09.01) and because of new developments within the field of microbial mutagenesis testing. Its purpose is to provide a guide for people who perform or evaluate microbial mutagenesis tests, but it is not intended for these recommendations to replace or diminish the usefulness of presently available protocols and procedures.

20 compounds identified in pulp mill effluents were screened for genetic activity in growing cells using Saccharomyces cerevisiae strains D7 and XV185-14C without and with S9. Nine compounds were positive in one or the other yeast strain (7 in D7; 2 in XV185-14C). One additional compound showed weak effects and two others showed elevated frequencies/survivor without absolute increases of mutants. The presence of S9 enabled detection of one positive and two weak effects, it enhanced the genetic activity of one compound in each strain, and it reduced the mutagenic effects of 4 others in strain D7. 7 of the 20 chemicals tested have been shown previously to be mutagenic in the Salmonella/mammalian-microsome assay. Of the 7 bacterial mutagens, 6 were positive and 1 had a weak effect in yeast.