OBJECTIVETo evaluate three alternative methods for LD50 test-Fixed Dose Procedure (FDP), the Acute Toxic Class Method (ATC) and Up and Down Procedure (UDP).

METHODSFemale SD rats (8-12 weeks of age, 160-200 g) were used. Three alternative methods from OECD were applied to assess 22 chemicals (10 cosmetic raw materials and 12 raw materials of personal and home care products). The toxicity ranking for tested chemicals was established according to Globally Harmonized System (GSH). The results LD50 test were compared for the consistency and correlation between alternative methods and traditional test.

RESULTSFor cosmetic raw materials, the concordance rate of the three alternative methods was 80% (8/10); for raw material of personal and home care products, the concordance rates of FDP, ATC and UDP was 91.7% (11/12), 75.0% (9/12) and 83.0% (10/12), respectively. The number of animals required in three alternative methods was significantly lower than that in traditional test (P < 0.05), but the time required in three alternative methods was significantly higher than that in traditional test (P < 0.05).

CONCLUSIONSHigh consistency and correlation were found between each alternative method and LD50 test. FDP may be more potential when applied to assess acute oral toxicity of cosmetic raw materials.

Administration, Oral ; Animals ; Cosmetics ; toxicity ; Dose-Response Relationship, Drug ; Female ; Hazardous Substances ; toxicity ; Lethal Dose 50 ; Rats ; Rats, Sprague-Dawley ; Toxicity Tests, Acute ; methods

This paper reviews the published literature that is concerned with color vision impairment from industrial and environmental exposure to neurotoxic substances, and we evaluated whether testing for color vision impairment could be an affordable procedure for assessing these neurotoxic effects. In general, most cases of congenital color vision impairment are red-green, and blue-yellow impairment is extremely rare. However, most of the acquired color vision impairment that is related to age, alcohol or environmental factors is blue-yellow impairment. Therefore, many studies have been performed to identify this relationship between exposure to neurotoxic substances, such as organic solvents and heavy metals, and the prevalence of blueyellow color vision impairment. The test for color vision impairment is known to be very sensitive to the early signs of nervous system dysfunction and this can be useful for making the early diagnosis of neurotoxic effects from exposure to very low concentrations of toxic substances.
*Color Perception Tests ; Color Vision Defects/*chemically induced/diagnosis ; Early Diagnosis ; Hazardous Substances/*toxicity ; Humans ; Neurotoxicity Syndromes/*diagnosis/pathology ; Solvents/adverse effects

BACKGROUNDSeveral studies have suggested that the exposure to cadmium (Cd) increased mortalities from renal diseases, cardiovascular diseases and malignant neoplasm, including lung cancer and prostate cancer among inhabitants living in Cd-polluted areas and factory workers. This study aimed to assess the influence of environmental exposure to Cd on long term outcome of inhabitants living in an area polluted by Cd.

METHODSA 22-year follow-up study was conducted with 3119 inhabitants (1403 men and 1716 women) living in the Cd polluted Kakehashi River basin in Japan. The subjects were divided into 4 groups according to the amount of urinary Cd level (< 3.0 µg/g creatinine (Cr), 3.0 - 4.9 µg/g Cr, 5.0 - 9.9 µg/g Cr, and ≥ 10.0 µg/g Cr). Mortality was calculated by the person-years method. Hazards ratios (HR) and 95% confidence intervals (CI) were assessed by the Cox's proportional hazard model.

RESULTSCompared with urinary Cd < 3.0 µg/g Cr group, the HR of 5.0 - 9.9 µg/g Cr and ≥ 10.0 µg/g Cr groups were significantly increased after adjustment for age in both sexes: 1.24 (95%CI 1.01 - 1.51) and 1.48 (95%CI 1.17 - 1.90) for men; 1.64 (95%CI 1.17 - 2.28) and 1.78 (95%CI 1.27 - 2.50) for women. The most frequent cause of death was malignant neoplasm in men and cardiovascular diseases in women. The significant increase in mortality risk for cardiovascular diseases was observed in the subjects with ≥ 10 µg/g Cr in both sexes: 1.79 for men (95%CI 1.02 - 3.12) and 2.38 for women (95%CI 1.11 - 5.07). When the subjects were divided into 2 categories (< 20 µg/g Cr and ≥ 20 µg/g Cr), the HR of the urinary Cd ≥ 20 µg/g Cr group for nephritis and nephrosis were 4.82 (95%CI 1.07 - 21.61) in men and 7.92 (95%CI 1.77 - 35.33) in women, respectively. The significant increase was not observed for malignant neoplasm.

CONCLUSIONThese results suggest a dose-response relationship between Cd body burden and mortality for cardiovascular diseases, cerebrovascular diseases and nephritis and nephrosis.

Aged ; Aged, 80 and over ; Cadmium ; toxicity ; Cardiovascular Diseases ; mortality ; Cerebrovascular Disorders ; mortality ; Environmental Exposure ; adverse effects ; Female ; Follow-Up Studies ; Hazardous Substances ; Humans ; Japan ; Male ; Middle Aged ; Nephritis ; mortality ; Nephrosis ; mortality ; Proportional Hazards Models ; Risk Factors

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a prototypic halogenated aromatic hydrocarbon (HAH), is known as one of the most potent toxicants. At least a part of its toxic effects appears to be derived from its ability to induce TNF-alpha production. However, the signaling pathway of TCDD that leads to TNF-alpha expression has not been elucidated. In this study, we investigated the signaling mechanism of TCDD-induced TNF-alpha expression in PMA-differentiated THP-1 macrophages. TCDD induced both mRNA and protein expression of TNF-alpha in a dose- and time-dependent manner. Alpha-Naphthoflavone (NF), an aryl hydrocarbon receptor (AhR) inhibitor, prevented the TCDD-induced expression of TNF-alpha at both mRNA and protein levels. Genistein, a protein tyrosine kinase (PTK) inhibitor, and PD153035, an EGFR inhibitor, also blocked the increase of TNF-alpha expression by TCDD, indicating the role of EGFR in TCDD-induced TNF-alpha expression. On the other hand, PP2, a c-Src specific inhibitor, did not affect TCDD-induced TNF-alpha expression. EGFR phosphorylation was detected as early as 5 min after TCDD treatment. TCDD-induced EGFR activation was AhR-dependent since co-treatment with alpha-NF prevented it. ERK was found to be a downstream effector of EGFR activation in the signaling pathway leading to TNF-alpha production after TCDD stimulation. Activation of ERK was observed from 30 min after TCDD treatment. PD98059, an inhibitor of the MEK-ERK pathway, completely prevented the TNF-alpha mRNA and protein expression induced by TCDD, whereas inhibitors of JNK and p38 MAPK had no effect. PD153035, an EGFR inhibitor, as well as alpha-NF significantly reduced ERK phosphorylation, suggesting that ERK activation by TCDD was mediated by both EGFR and AhR. These results indicate that TNF-alpha production by TCDD in differentiated THP-1 macrophages is AhR-dependent and involves activation of EGFR and ERK, but not c-Src, JNK, nor p38 MAPK. A signaling pathway is proposed where TCDD induces sequential activation of AhR, EGFR and ERK, leading to the increased expression of TNF-alpha.
Animals ; Benzoflavones/pharmacology ; Cell Differentiation ; Cell Line, Tumor ; Enzyme Activation ; Genistein/pharmacology ; Hazardous Substances/*toxicity ; Humans ; MAP Kinase Signaling System/drug effects/physiology ; Macrophages/*metabolism ; Mice ; Phosphorylation ; Pyrimidines/pharmacology ; Quinazolines/pharmacology ; RNA, Messenger/metabolism ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Receptors, Aryl Hydrocarbon/antagonists & inhibitors ; Signal Transduction ; Tetrachlorodibenzodioxin/*toxicity ; Tumor Necrosis Factor-alpha/*biosynthesis ; src-Family Kinases/antagonists & inhibitors/metabolism