Rodent Toxicity Studies Research Articles

Safety evaluation of food enzyme glucan 1,4-α-maltohydrolase produced with a genetically modified Bacillussubtilis (strain MAM).

The food enzyme considered in this opinion is a glucan 1,4‐α‐maltohydrolase (maltogenic α‐amylase; EC 3.2.1.133) produced with the genetically modified Bacillus subtilis strain MAM by the company DSM Food Specialties B. V. The food enzyme contains neither the production microorganism nor recombinant DNA; therefore, no environmental risk assessment is required. However, the Panel emphasises that this conclusion only covers the food enzyme recovered via filter press. The glucan 1,4‐α‐maltohydrolase is intended for use in baking processes. Based on the maximum use levels recommended and individual consumption data from the EFSA Comprehensive European Food Consumption Database, dietary exposure to the food enzyme‐total organic solids (TOS) was estimated to be up to 0.175 mg TOS/kg body weight (bw) per day in European populations. The systemic toxicity was assessed by means of a repeated dose 90‐day oral toxicity study in rodents. A no observed adverse effect level (NOAEL) was derived (986 mg TOS/kg bw per day for both males and females), which, compared with the dietary exposure, results in a sufficiently high margin of exposure. The allergenicity was evaluated by comparing the amino acid sequence to those of known allergens; one match was found. However, the Panel considered that there are no indications for food allergic reactions to this glucan 1,4‐α‐maltohydrolase by dietary exposure. No safety concerns were identified in relation to the genetic modifications, the manufacturing process, the compositional data provided, as well as the exposure, allergenicity and systemic toxicity assessments. However, owing to the incompleteness of the genotoxicity data, the Panel is not able to conclude on the safety of the food enzyme.

Safety evaluation of the food enzyme maltogenic amylase from a genetically modified Bacillussubtilis (strain NZYM-SM).

The food enzyme considered is a maltogenic amylase (glucan 1,4‐α‐maltohydrolase; EC 3.2.1.133) produced with the genetically modified Bacillus subtilis strain NZYM‐SM by Novozymes A/S. The food enzyme contains neither the production organism nor recombinant DNA. The maltogenic amylase is intended for use in baking processes and starch processing for glucose syrups production. Based on the maximum use levels recommended for the food processes and individual consumption data from the EFSA Comprehensive European Food Consumption Database, dietary exposure to the food enzyme–Total Organic Solids (TOS) was estimated to be up to 0.168 mg TOS/kg body weight (bw) per day in European populations. The food enzyme did not induce gene mutations in bacteria or chromosomal aberrations in human lymphocytes. The subchronic toxicity was assessed by means of a repeated dose 90‐day oral toxicity study in rodents. A no observed adverse effect level (NOAEL) was derived (320 mg TOS/kg bw per day), which, compared with the dietary exposure, results in a sufficiently high margin of exposure. The allergenicity was evaluated by searching for similarity of the amino acid sequence to those of known allergens. Three matches to occupational respiratory allergens were found, however, the Panel considered that there are no indications for food allergic reactions to the food enzyme. Based on the genetic modifications performed, the manufacturing process, the compositional and biochemical data provided, the dietary exposure assessment, the findings in the toxicological studies and allergenicity assessment, the Panel concluded that the food enzyme maltogenic amylase from Bacillus subtilis strain NZYM‐SM does not give rise to safety concerns under the intended conditions of use.

Safety evaluation of the food enzyme endo-1,4-β-xylanase from a genetically modified Aspergillusniger (strain XEA).

The food enzyme is an endo‐1,4‐β‐xylanase (EC 3.2.1.8) produced with a genetically modified strain of Aspergillus niger (strain XEA), by DSM Food Specialities B.V. The food enzyme is intended to be used in baking and brewing processes. Based on maximum use levels recommended for the food processes and individual consumption data from the EFSA Comprehensive European Food Consumption Database, dietary exposure to the food enzyme–total organic solids (TOS) was estimated to be up to 0.310 mg TOS/kg body weight per day in European populations. Genotoxicity tests with the food enzyme did not indicate a genotoxic concern. A repeated dose 90‐day oral toxicity study in rodents, carried out with this endo‐1,4‐β‐xylanase, showed no concern with respect to systemic toxicity. The allergenicity was evaluated by searching for similarity of the amino acid sequence to those of known allergens; no match was found. The Panel considers that there are no indications for allergic sensitisation and elicitation reactions by dietary exposure to the food enzyme endo‐1,4‐β‐xylanase. Based on the microbial source, the genetic modifications performed, the manufacturing process, the compositional and biochemical data provided, the dietary exposure assessment, the findings in the toxicological studies and the allergenicity assessment, the Panel concludes that this food enzyme does not give rise to safety concerns under the intended conditions of use.

Safety evaluation of the food enzyme xylanase from a genetically modified Bacillussubtilis strain TD160(229).

The food enzyme considered in this opinion is an endo‐1,4‐β‐xylanase (EC 3.2.1.8) produced with a genetically modified Bacillus subtilis strain from Puratos N.V. (Belgium). The genetic modifications do not raise safety concerns. The food enzyme contains neither the production organism nor recombinant DNA. The endo‐1,4‐β‐xylanase is intended to be used in baking processes. Based on the maximum use levels recommended for the baking processes, dietary exposure to the food enzyme–total organic solids (TOS) was estimated on the basis of individual data from the EFSA Comprehensive European Food Consumption Database. This exposure estimate is up to 0.008 mg TOS/kg body weight per day in European populations. The food enzyme did not induce gene mutations in bacteria nor clastogenic activity in human lymphocytes. Therefore, there is no concern with respect to genotoxicity. The subchronic toxicity was assessed by means of a repeated dose 90‐day oral toxicity study in rodents. A no observed adverse effect level was derived, which, compared with the dietary exposure, results in a sufficiently high margin of exposure. The allergenicity was evaluated by searching for similarity of the amino acid sequence to those of known allergens; no matches were found. The Panel considered that there are no indications for food allergic reactions to this xylanase. Based on the microbial source, genetic modifications performed, the manufacturing process, the compositional and biochemical data provided, the findings in the toxicological studies and allergenicity assessment, this food enzyme does not give rise to safety concerns under the intended conditions of use.

Sub-chronic oral toxicity study of matrix tablets of micronized domperidone formulation in rodents

The present study deals with sub-chronic oral toxicity studies in rodents of micronized domperidone matrix drug formulation. The matrix tablet of domperidone was formulated by using different polymers. After the completion of the formulation the matrix tablets the tablets were crushed into powder and a homogeneous suspension was prepared. The suspension was administered to rats at different dosages according to the study plan. During the studies animals’ weight were taken at periodically. After 28th day of study period the animal’s blood was collected for pathological and biological analysis. At the termination of study, all the animals were sacrificed and vital organs were taken out for autopsy studies. After the thorough studies the results shows that that the micronized formulation did not produce any significant toxicity in rodents.

Regulatory Forum Opinion Piece*: Effective Brain Trimming for Regulatory-type Nonclinical Toxicity Studies.

Regulatory guidances for nonclinical toxicity testing require brain evaluation but do not require a specific analytical strategy. The Society of Toxicologic Pathology (STP) has produced "best practice" recommendations for brain sampling and processing in general toxicity (GT) studies in adult rodents and nonrodents as well as developmental neurotoxicity (DNT) studies in rodents. This article explains acceptable brain trimming strategies as described in these 2 STP documents. Figures in the DNT and GT "best practices" illustrate coronal brain trimming at specific levels as defined by discrete external and internal anatomic landmarks. However, the text of both "best practice" papers states that institutions may choose different brain trimming levels or other planes (e.g., a longitudinal orientation) as long as key structures are sampled and trimming is consistent among individuals across the study. The STP-recommended number of brain levels to evaluate (7 or 8 coronal sections for GT and DNT studies, respectively) may need to be increased if neurotoxicity is considered possible or likely based on in-life clinical findings or other risk factors (chemical structure, known mode of action, etc.).

Safety evaluation of the food enzyme pullulanase from Pullulanibacillusnaganoensis strain AE-PL.

The food enzyme considered in this opinion is a pullulanase (pullulan 6‐α‐glucanohydrolase; EC 3.2.1.41) produced with a non‐genetically modified Pullulanibacillus naganoensis (strain AE‐PL) by Amano Enzyme Inc. (Japan). The pullulanase food enzyme is intended to be used in starch processing for the production of glucose syrups. Since residual amounts of total organic solid (TOS) in glucose syrups are removed by filtration and purification during starch processing, dietary exposure assessment was not performed. Genotoxicity tests made with the food enzyme indicated no genotoxic potential. A repeated dose 90‐day oral toxicity study in rodents, carried out with the food enzyme, showed minor effects that were considered to be of no biological relevance. The allergenicity was evaluated by comparing the amino acid sequence to those of known allergens and no match was found. The Panel considered that there are no indications for food allergic reactions to dietary intake of this food enzyme. Based on the removal of residual amounts of TOS from glucose syrups, consumer exposure is not expected. In addition, the safety of the manufacturing process, the compositional and biochemical data lead the Panel to conclude that the food enzyme pullulanase from P. naganoensis (strain AE‐PL) does not give rise to safety concerns under the intended conditions of use.

Safety of Ecklonia cava phlorotannins as a novel food pursuant to Regulation (EC) No258/97.

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on the safety of Ecklonia cava phlorotannins (marketed as SeaPolynol™) as a novel food submitted pursuant to Regulation (EC) No 258/97. The novel food is a phlorotannin‐rich alcohol extract of Ecklonia cava, which is an edible marine brown alga species. The information provided on the composition, the specifications, the production process and the batch‐to‐batch variability of the novel food is sufficient and does not raise safety concerns. The intention is to market the novel food as a food supplement for healthy individuals over the age of 12 years. A subchronic repeated dose oral toxicity study in rodents tested the novel food at daily doses of 0, 375, 750 and 1,500 mg/kg body weight (bw). The Panel considers the mid‐dose as the no‐observed‐adverse‐effect‐level (NOAEL) of the study. Taking into account this NOAEL of 750 mg/kg bw per day and by applying an uncertainty factor of 200, the Panel considers an intake level of 3.75 mg/kg bw per day as safe. The Panel concludes that the novel food, Ecklonia cava phlorotannins, is safe for the use in food supplements at a maximum daily intake level of 163 mg/day for adolescents from 12 to 14 years of age, 230 mg/day for adolescents above 14 years of age and 263 mg/day for adults.

Safety of dried aerial parts of Hoodia parviflora as a novel food pursuant to Regulation (EC) No258/97.

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on the dried aerial parts of Hoodia parviflora as a novel food (NF) submitted pursuant to Regulation (EC) No 258/97. The information provided on the composition, the specifications, the production process, the batch‐to‐batch variability and the stability of the NF is sufficient and does not raise safety concerns. The applicant intends to use the NF in a number of energy‐reduced/sugar‐free/no‐added‐sugar foods in quantities of up to 15 mg per serving. The applicant also proposes to provide the NF as a food supplement. The target population proposed by the applicant is adults. The highest intake estimates were found in the group of elderly (≥ 65 years) individuals, with a high intake of 1.0 mg/kg body weight (bw) per day. One 90‐day toxicity study in rodents was provided from which a benchmark dose lower confidence limit (BMDL 05) of 53.5 mg/kg bw per day was derived for effects of the NF on bodyweight. The Panel concludes that the addition of the NF to foods as a food ingredient at the uses and use levels as proposed by the applicant would exceed intake levels considered safe in humans. The Panel considers that the NF is safe to be used as a food supplement at a maximum dose of 9.4 mg/day. The target population is adults.

Safety evaluation of the food enzyme pullulanase from genetically modified Bacillus subtilis strain NZYM-AK.

The food enzyme considered in this opinion is a pullulanase (pullulan 6‐α‐glucanohydrolase; EC 3.2.1.41), produced with the genetically modified Bacillus subtilis strain NZYM‐AK by Novozymes A/S (Denmark). The pullulanase food enzyme is intended to be used in starch processing for the production of glucose syrups. Since the residual amounts of total organic solids (TOS) in glucose syrups after filtration and purification during starch processing were considered negligible, no dietary exposure was calculated. Genotoxicity tests made with the food enzyme indicated no genotoxic concern. A repeated dose 90‐day oral toxicity study in rodents, carried out with a pullulanase produced with a predecessor strain, showed no concern with respect to systemic toxicity. The allergenicity was evaluated by searching for similarity of the amino acid sequence to those of known allergens; no match was found. The Panel considers that there are no indications for allergic reactions. Based on the microbial source, genetic modifications performed, the manufacturing process, the compositional and biochemical data provided, the findings in the toxicological studies and allergenicity assessment, the Panel concludes that this food enzyme does not give rise to safety concerns under the intended conditions of use.

Characterization of Zinc Carbonate Basic as a Source of Zinc in a Rodent Study Investigating the Effects of Dietary Deficiency or Excess

ABSTRACTZinc deficiency and excess can result in adverse health outcomes. There is conflicting evidence regarding whether excess or deficient zinc in the diet can contribute to carcinogenicity. The objective of this study was to characterize zinc carbonate basic for use as a source of dietary zinc in a rodent toxicity and carcinogenicity study investigating the effects of zinc deficiency and excess. Because of the complex chemistries of zinc carbonate basic compounds, inconsistent nomenclature, and literature and reference spectra gaps, it was necessary to use multiple analytical techniques, including Karl Fischer titration, combustion analysis, inductively coupled plasma–optical emission spectrometry, X-ray diffraction, infrared spectroscopy, X-ray fluorescence spectrometry, and thermogravimetric analysis to characterize the test article. Based on the collective evidence and through the process of elimination, the test article was found to be composed mainly of zinc carbonate basic with zinc oxide as a minor component. The zinc content was determined to be 56.6% (w/w) with heavy metals such as arsenic, cadmium, mercury, and lead below the limit of quantitation of less than or equal to 0.01%. The test material was stable at ambient temperature. Based on the work described in this manuscript, the test article was suitable for use as a source of zinc in studies of deficiency and excess in the diet.

Safety evaluation of the food enzyme endo‐1,4‐β‐xylanase from genetically modified Aspergillus niger strain XYL

The food enzyme considered in this opinion is an endo‐1,4‐β‐xylanase (EC 3.2.1.8) produced with a genetically modified strain of Aspergillus niger. The genetic modifications do not give rise to safety concerns. The food enzyme contains neither the production organism nor recombinant DNA. The endo‐1,4‐β‐xylanase is intended to be used in baking processes. Based on the maximum use levels recommended for the respective food process, dietary exposure to the food enzyme–total organic solids (TOS) was estimated on the basis of individual data from the EFSA Comprehensive European Food Consumption Database. This exposure estimate is below 0.013 mg TOS/kg body weight (bw) per day in European populations. No safety concerns were identified in relation to the genetic modifications performed, the manufacturing process, the compositional and biochemical data provided, allergenicity and exposure assessments. The allergenicity was evaluated by comparing the amino acid sequence to those of known allergens; no match was found. The Panel considered that the likelihood of allergic reactions to dietary intake of endo‐1,4‐β‐xylanase is low and, therefore, does not give rise to safety concerns. The systemic toxicity was assessed by means of a repeated dose 90‐day oral toxicity study in rodents. A no observed adverse effect level was derived (4,095 and 4,457 mg TOS/kg bw per day for males and females, respectively), which, compared with the dietary exposure, results in a sufficiently high margin of exposure. However, the genotoxicity data were incomplete. Due to the absence of the recommended combination of microbial strains used in the Ames test (i.e. lack of Salmonella Typhimurium TA102 and Escherichia coli WP2), no conclusions can be drawn on potential DNA oxidising or cross‐linking mechanisms giving rise to gene mutations. Consequently, no final conclusions can be drawn on genotoxicity.

Scientific opinion on an application by Monsanto (EFSA-GMO-NL-2013-114) for the placing on the market of a herbicide-tolerant genetically modified cotton MON88701 for food and feed uses, import and processing under Regulation (EC) No1829/2003.

Cotton MON 88701 was developed through Agrobacterium tumefaciens‐mediated transformation to express the dicamba mono‐oxygenase (DMO) protein, conferring tolerance to dicamba, and the phosphinothricin N‐acetyltransferase PAT protein, conferring tolerance to glufosinate ammonium‐based herbicides. The molecular characterisation data and bioinformatics analyses did not identify issues requiring further assessment for food/feed safety. The agronomic and phenotypic characteristics tested revealed no relevant differences between cotton MON 88701 and its conventional counterpart. Since complete compositional results were reported for only three sites, the EFSA Panel on Genetically Modified Organisms (GMO Panel) is not in the position to complete the assessment of the compositional analysis. Moreover, as no 28‐day toxicity study in rodents on the MON 88701 DMO protein was provided, the GMO Panel is not in the position to complete the safety assessment of this protein in cotton MON 88701. Consequently, the GMO Panel cannot complete the toxicological, allergenicity and nutritional assessment of food/feed derived from cotton MON 88701. The safety assessment identified no concerns regarding the potential toxicity and allergenicity of the PAT protein newly expressed in cotton MON 88701. Considering the routes of exposure and limited exposure levels, the GMO Panel concludes that cotton MON 88701 would not give rise to safety concerns in the event of accidental release of viable seeds into the environment. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of cotton MON 88701. In conclusion, in the absence of an appropriate comparative assessment and an appropriate assessment of the MON 88701 DMO protein, the GMO Panel is not in a position to complete its food/feed risk assessment of cotton MON 88701. The GMO Panel concludes that the cotton MON 88701 is unlikely to have any adverse effect on the environment in the context of the scope of the application.

Re-evaluation of locust bean gum (E410) as a food additive.

Following a request from European Commission, the EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion re‐evaluating the safety of locust bean gum (E 410) as a food additive. Locust bean gum (E 410) is an authorised food additive in the EU. Locust bean gum (E 410) as specified in the Commission Regulation (EU) No 231/2012 is derived from the ground endosperm of the seeds of the strains of carob tree, Ceratonia siliqua (L.) Taub. (Family Leguminosae). An acceptable daily intake (ADI) ‘not specified’ was allocated by the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA) in 1981. Although not evaluated by the Scientific Committee for Food (SCF), it was accepted by the SCF in 1991 for use in weaning food, and in 1994, in infant formulae for special medical purposes. Locust bean gum is practically undigested, not absorbed intact, but significantly fermented by enteric bacteria in humans. No adverse effects were reported in 90‐day toxicity and carcinogenicity studies in rodents at the highest doses tested and there was no concern with respect to the genotoxicity and to reproductive and developmental toxicity of locust bean gum (E 410). The Panel concluded that there is no need for a numerical ADI for locust bean gum (E 410), and that there is no safety concern for the general population at the refined exposure assessment for its reported uses as a food additive. However, infants and young children consuming foods for special medical purposes may show a higher susceptibility to gastrointestinal effects of locust bean gum due to their underlying medical condition. The Panel concluded that the available data do not allow an adequate assessment of the safety of locust bean gum (E 410) in these foods for infants and young children.

The repeated-dose 90-day study oral toxicity study in rodents (OECD TG408) as a tool to investigate toxicological effects of the whole genetically modified (GM) food/feed: Differences from the 90-day study on chemicals and challenges

The repeated-dose 90-day study oral toxicity study in rodents (OECD TG408) as a tool to investigate toxicological effects of the whole genetically modified (GM) food/feed: Differences from the 90-day study on chemicals and challenges

Abstract 4798: Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL

Abstract Interleukin-1 receptor associated kinases (IRAKs) are serine/threonine protein kinases belonging to the tyrosine-like kinase (TLK) family. IRAKs function as mediators of Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and play an important role in innate immune signaling. TLR/IL-1R stimulation leads to recruitment of MYD88, an adaptor molecule, to the activated receptor complex, which then complexes with IRAK4 and activates IRAK1. TRAF6 is then activated by IRAK1 leading to NFkB activation. Recent studies have reported the occurrence of gain of function oncogenic mutation (L265P) in MYD88 in ∼30% of activated B cell diffuse large B-cell lymphoma(ABC DLBCL) and ∼90% of Waldenstrom's macroglobulinemia (WM) leading to constitutive activation of IRAK4 and NFkB pathway. Among the DLBCL subtypes (GCB, ABC DLBCL and PMBL), ABC DLBCL is the most refractory. Inhibition of constitutive IRAK4 signalling can be used as a therapeutic strategy to treat ABC DLBCL Small molecule inhibitors of IRAK4 were synthesized based on hits originating from Aurigene's compound library. Structure guided drug design approach was used to further improve the potency. Lead compounds demonstrated moderate to very high selectivity towardsIRAK4 (S35 score of 0.03) when screened against a large panel of 329 kinases. Aurigene's lead compounds have excellent PK profile and good oral bioavailability in mice, leading to good in-vivo activity in TLR4 induced cytokine release model. Selected lead compounds were tested in a OCI-Ly3 xenograft model, which has a MYD88(L265P) mutation leading to constitutive activation of IRAK4 signaling. An advanced lead compound has demonstrated excellent efficacy in OCI-Ly3 model, with tumor stasis at low doses and tumor regression at higher doses. The compound is well tolerated and has a good therapeutic window as determined in a 14 day rodent toxicity study. In summary, a selective IRAK4 inhibitor has been identified with excellent efficacy and good safety profile. Citation Format: Wesley Roy Balasubramanian, Venkateshwar Rao Gummadi, Kavitha Nellore, Subhendu Mukherjee, Sivapriya Marappan, Aravind Basavaraju, Bharathi Raja Ainan, Girish Daginakatte, Sreevalsam Gopinath, Sanjeev Giri, Thomas Antony, Shekar Chelur, Susanta Samajdar, Chetan Pandit, Murali Ramachandra. Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4798.

Aqueous extract of Senecio candicans DC induce liver and kidney damage in a sub-chronic oral toxicity study in Wistar rats

Senecio candicans DC. (Asteraceae) is used as a remedy for gastric ulcer and stomach pain in the Nilgiris, district, Tamil Nadu. The present investigation was carried out to evaluate the sub-chronic toxicity of an aqueous extract of Senecio candicans (AESC) plant in Wistar albino rats. The study was conducted in consideration of the OECD 408 study design (Repeated Dose 90-Day Oral Toxicity Study in Rodents) and the extract was administered via gavage at doses of 250, 500 or 750 mg/kg body weight per day for 90-days. Hematological, biochemical parameters were determined on days 0, 30, 60 and 90 of administration. Animals were euthanized after 90 d treatment and its liver and kidney sections were taken for histological study. The results of sub-chronic study showed significant increase (P < 0.05) in serum uric acid, creatinine, aspartate transaminase (AST) and alanine transaminase (ALP) levels. Histological examination of liver showed mild mononuclear infiltration in the portal trait, enlarged nucleus around the central vein and mild loss of hepatocyte architecture in rats treated with 750 mg/kg of AESC. Histological examination of kidney showed focal interstitial fibrosis, crowding of glomeruli and mild hydropic change with hypercellular glomeruli in rats treated with 750 mg/kg of AESC. However, no remarkable histoarchitectural change in hepatocytes and glomeruli were observed in rats treated with lower concentrations (250 and 500 mg/kg b.w.) of AESC compared to control group animals. The no-observed adverse effect level (NOAEL) of AESC in the present study was 500 mg/kg b.w. Signs of toxic effects are evident from the current study. Although AESC contains low concentrations of PA, findings from this study suggest that regular consumers of herbal remedies derived from this plant may develop kidney and liver toxicity. Further studies on the isolation and characterization of PAs are necessary to determine the safe dose level of the extract for therapeutic use in traditional medicine.

Numeric Estimates of Teratogenic Severity from Embryo-Fetal Developmental Toxicity Studies.

A developing organism exposed to a toxicant will have a response that ranges from none to severe (i.e., death or malformation). The response at a given dosage may be termed teratogenic (or developmental toxic) severity and is dependent on exposure conditions. Prenatal/embryo-fetal developmental (EFD) toxicity studies in rodents and rabbits are the most consistent and definitive assessments of teratogenic severity, and teratogenesis screening assays are best validated against their results. A formula is presented that estimates teratogenic severity for each group, including control, within an EFD study. The developmental components include embryonic/fetal death, malformations, variations, and mean fetal weight. The contribution of maternal toxicity is included with multiplication factors to adjust for the extent of mortality, maternal body weight change, and other parameters deemed important. The derivation of the formula to calculate teratogenic severity is described. Various EFD data sets from the literature are presented to highlight considerations to the calculation of the various components of the formula. Each score is compared to the concurrent control group to obtain a relative teratogenic severity. The limited studies presented suggest relative scores of two- to <fivefold higher than control have detectable but a low level of teratogenic severity, and scores ≥ fivefold higher than control have increasingly more severe teratogenicity. Such scores may help refine the concept of an exposure-based validation list for use by proponents of screening assays (Daston et al., 2014) by estimating the severity of "positive" exposures, or in other situations by defining the severity of a LOAEL (lowest observed adverse effect level).

Reversal of parenteral anticoagulants by PEG41-PMAPTAC53: characteristics, efficacy and toxicity studies in rodents

Reversal of parenteral anticoagulants by PEG41-PMAPTAC53: characteristics, efficacy and toxicity studies in rodents

Acrylamide in Foods Generated through Heating (Contaminants).

The Food Safety Commission of Japan (FSCJ) conducted a risk assessment on acrylamide (AA) (CAS No. 79-06-1) in foods generated through heating, as a self-tasking risk assessment. In rodent toxicity studies, major adverse effects were observed on neurotoxicity and male reproductive toxicity. Statistically significant increases in incidences were observed in the carcinogenicity studies in Harderian gland, mammary gland, lung and forestomach in mice, and in mammary gland, thyroid and testis in rats. Positive results were also obtained from in vitro and in vivo genotoxicity studies of AA and glycidamide (GA). Therefore, FSCJ recognized AA as a genotoxic carcinogen. Judging from the dietary AA intake among Japanese people, the non-neoplastic risk is extremely low because of sufficient margins of exposure (MOEs). The neoplastic risk, however, could not be excluded due to the insufficient MOEs, although no clear evidence on human health effect have been provided from the epidemiological studies. It is important to note that no consistent relationships between AA exposure and cancer incidences have been observed even in the studies focusing on the highly exposed populations in occupational settings. FSCJ thus concluded that continual efforts are necessary to reduce dietary AA intakes in accordance with the principle of ALARA (as low as reasonably achievable) from the viewpoint of public health.