Skin sensitization testing in potency and risk assessment.

The purpose of this article is to review, and make recommendations for, the use of relevant skin sensitization test methods, for the purposes of determination of relative potency and the threshold dose necessary for the induction of skin sensitization, and for risk assessment. In addressing the first area, the utility of three guinea pig tests (the guinea pig maximization test, the occluded patch test, and the open epicutaneous test) of the local lymph node assay (LLNA) and of human volunteer testing for the assessment of relative potency and identification of thresholds for sensitization were considered. The following conclusions were drawn. (1) Although attempts have been made to modify the guinea pig maximization test for the purposes of deriving dose-response relationships, this method is usually unsuitable for determination of relative sensitizing potency. (2) Guinea pig methods that do not require the use of adjuvant and which employ a relevant route of exposure (the occluded patch test and the open epicutaneous test) are more appropriate for the assessment of relative skin-sensitizing potency. (3) The LLNA is suitable for the determination of relative skin sensitizing potency, and the adaptation of this method for derivation of comparative criteria such as EC3 values (the estimated concentration of test chemical required to induce a stimulation index of 3 in the LLNA) provides an effective and quantitative basis for such measurements. (4) For all the methods identified above, potency is assessed relative to other chemical allergens of known skin sensitizing potential. The estimation of likely threshold concentrations is dependent upon the availability of suitable benchmark chemicals of known potency for human sensitization. (5) Human testing (and specifically, the Human Repeat Insult Patch Test) can provide information of value in confirming the absence of skin sensitizing activity of formulations and products under specific conditions of use and exposure. Based on the above, the following recommendations are made. (1) If results are already available from suitable guinea pig tests, then judicious interpretation of the data may provide information of value in assessing relative skin sensitizing potency. This option should be explored before other analyses are conducted. (2) The LLNA is the recommended method for new assessments of relative potency, and/or for the investigation of the influence of vehicle or formulation on skin sensitizing potency. (3) Whenever available, human skin sensitization data should be incorporated into an assessment of relative potency. With respect to risk assessment, the conclusion drawn is that all the available data on skin-sensitizing activity in animals and man should be integrated into the risk-assessment process. Appropriate interpretation of existing data from suitable guinea pig studies can provide valuable information with respect to potency, as the first step in the development of a risk assessment. However, for de novo investigations, the LLNA is the method favored for providing quantitative estimations of skin-sensitizing potency that are best suited to the risk assessment process. Finally, human testing is of value in the risk assessment process, but is performed only for the purposes of confirming product safety.

Neuroimmunotoxicology: humoral assessment of neurotoxicity and autoimmune mechanisms.

The interactions between the nervous and immune systems have been recognized in the development of neurodegenerative disease. This can be exploited through detection of the immune response to autoantigens in assessing the neurotoxicity of environmental chemicals. To test this hypothesis, the following questions were addressed. a) Are autoantibodies to nervous system (NS) antigens detected in populations exposed to environmental or occupational chemicals? In sera of male workers exposed to lead or mercury, autoantibodies, primarily IgG, to neuronal cytoskeletal proteins, neurofilaments (NFs), and myelin basic protein (MBP) were prevalent. These findings were confirmed in mice and rats exposed to either metal. b) Do autoantibodies to NS antigens relate to indices of exposure? In humans exposed to either metal, and similarly in exposed rats, titers of IgG against NFs and MBP significantly correlated with blood lead or urinary mercury, the typical indices of exposure. c) Do autoantibodies correlate with sensorimotor deficits? In workers exposed to lead or mercury, a significant correlation was observed between IgG titers and subclinical deficits. Doses of metals used in rat exposures were subclinical, suggesting that autoantibodies may be predictive of neurotoxicity. d) Is the detection indicative of nervous system pathology? In rats exposed to metals, histopathology indicated central nervous system (CNS) and peripheral nervous system (PNS) damage. In addition there was evidence of astrogliosis, which is indicative of neuronal damage in the CNS, and the presence of IgG concentrated along the blood-brain barrier, as indicated by immunostaining for antibodies. e) Are immune responses to NS antigens pathogenic? Immunoglobulin fractions from rat and human sera interfered with neuromuscular function. These studies suggest that the detection of autoantibodies to NS-specific antigens may be used to monitor the development of neurotoxicity to environmental chemicals and that immune mechanisms may be involved in the progression of neurodegeneration.

Developmental toxicity assessment of C8 iso acid in CD rats: relevance to embryotoxic aliphatic carboxylic acids.

Cekanoic C8 acid (CAS RN 25103-52-0) is a complex isomeric substance containing several aliphatic carboxylic acids, primarily dimethyl hexanoic acid. Because Cekanoic C8 acid is a structural isomer of octanoic acid, its potential for developmental toxicity was investigated in CD (Sprague-Dawley) rats. Cekanoic C8 acid was administered by oral gavage to 25 confirmed-mated females at doses of 0, 200, 400, and 800 mg/kg/day on gestation days (GD) 6-15, based on a range-finding experiment. Maternal body weights, food consumption, and clinical observations were recorded throughout gestation. On GD 21, cesarean sections were performed and the uterine contents removed and subjected to conventional teratological evaluation. At 800 mg/kg/day, maternal body weight gain and food consumption were reduced during the exposure period, and clinical signs were evident. There were no significant differences in fetal weight, malformation incidence, or fetal viability in any of the experimental groups. There was a statistically significant increase in the incidence of total variations in the 800-mg/kg/day group, which was within the historical control range of this laboratory and not considered biologically significant. These results indicate that, unlike related compounds, Cekanoic C8 acid was not teratogenic or a selective developmental toxicant in rats. This is the first report of a dimethyl substituted aliphatic acid being evaluated for developmental toxicity in a definitive study. The results are consistent with a structure-teratogenicity relationship for aliphatic acids, indicating that side-chain branching larger than a methyl group is required to elicit teratogenic effects. This study established a maternal no-observable-adverse-effect level (NOAEL) for Cekanoic C8 acid at 400 mg/kg/day and a developmental NOAEL at 800 mg/kg/day.

An assessment of the tumorigenic properties of a Hudson County soil sample heavily contaminated with hexavalent chromium.

During much of this century, Hudson County, New Jersey, was a major center for the processing of chromium ore. Some of the residue from this processing was used in landfills and in construction materials throughout the county and, in some cases, in highly populated areas. Given that it is widely accepted that exposure to hexavalent chromium compounds poses a risk for the development of respiratory-tract cancer, concerns were raised that individuals who worked or resided in chromium-contaminated areas might be at increased risk for the development of respiratory cancer. To address these concerns, we evaluated a Hudson County soil sample-heavily contaminated with chromium ore residue (Cr(+6) concentration at 5 895 mg/kg)-with respect to its carcinogenic potential to the respiratory tract of Sprague-Dawley rats. Groups of animals were given repeated intratracheal exposures to one of four materials: (1) Hudson County chromium-contaminated soil (CCS), (2) CCS augmented with calcium chromate (CaCrO4), (3) CaCrO4 alone, or (4) control soil. Nominal total doses of Cr(+6) for each respective group were 324 microg/kg, 7,975 microg/kg, 8,700 microg/kg, and 0.02 microg/kg. Incidences of malignant tumors and nephritis were not elevated in any group. Four primary lung tumors appeared in animals that received CCS + CaCrO4, and one primary lung tumor appeared in the group treated with CaCrO4 alone. These incidences were not significant statistically, but the rare spontaneous occurrence of these tumors in Sprague-Dawley rats suggested that they were treatment related. No primary lung tumors appeared in the control or CCS-treated groups.

A model immunization demonstration for preschoolers in an inner-city barrio, San Diego, California, 1992-1994.

An immunization demonstration project was conducted in an inner-city Latino neighborhood in San Diego to address underimmunization of children of preschool age. The project attempted interventions on consumer, provider, and system levels to reduce barriers to immunization and raise immunization rates. Free walk-in immunization clinics with emphasis on cultural sensitivity and that incorporated computerized reminder/recall were established. An educational series was offered to community health center (CHC) providers, and extensive community-based outreach and education took place in schools, churches, a WIC site, etc. Evaluation activities included preintervention and postintervention provider knowledge, attitudes, and practice surveys, CHC chart audits, and household surveys in the intervention ZIP code area and a control ZIP code area. Immunization coverage for 4DPT, 3OPV, and 1MMR (4:3:1) among two-year-olds increased significantly from 37% to 50% overall, and to 59% in the 1991 birth cohort in the intervention area compared to a one percentage point overall increase in the control area. Coverage improved significantly and missed opportunities decreased in one intervention CHC that participated most actively in educational inservices. While the Year 2000 U.S. Public Health Service objective of 90% 4:3:1 coverage for two-year-olds was not achieved over the 21-month course of the project, the results approached the 1996 single-antigen objectives. This demonstration underscores the importance of multilevel interventions including low cost, no appointment, and culturally appropriate immunization services for the indigent; the use of computerized reminder systems; and provider assessment, education, and feedback in the effort to raise preschool immunization levels. Medical Subject Headings (MeSH): immunization, preschool-age children, health promotion, provider education, immunization monitoring and follow-up systems, pediatric immunization standards, household surveys.

[A community referral system for the permanent program of universal vaccination]. / Sistema comunitario de referencia para el programa continuo de vacunación universal.

This article describes a community referral system for the permanent immunization program, tested in Tijuana, Baja California, Mexico, by the Regional Nucleus for Health Systems Development (NUREDESS-Norte). The model was designed to facilitate the participation of the intermediate organizations that make up the community in urban settings. Through appropriate technology, health counselors identify with precision, ease and rapidity the specific immunization needs of pre-school age children. The counselors also help diminish the barriers in the way to service access, and follow-up the children at highest risk.

Measles epidemic from failure to immunize.

During 1988 through 1990, California experienced its worst measles epidemic in more than a decade, with 16,400 reported cases, 3,390 hospital admissions, and 75 deaths. More than half of the patients were younger than 5 years; the highest incidence was among infants younger than 12 months. The epidemic centered in low-income Hispanic communities in southern and central California. The major cause of the epidemic was low immunization levels among preschool-aged children and young adults. Rates of complications, admission to hospital, and death were surprisingly high. Outbreak control efforts met with indeterminate success. Problems with these efforts included insufficient funding early in the epidemic and disappointing public response to community-based immunization campaigns. The cost of medical care and outbreak control for the epidemic is conservatively estimated at $30.9 million. Unless the level of immunization in preschool-aged children is increased, this type of epidemic will probably recur.

Risk factors for invasive Haemophilus influenzae type b in Los Angeles County children 18-60 months of age.

Potential factors that confer risk or protection for invasive Haemophilus influenzae type b disease were evaluated in Los Angeles County children 18-60 months of age by case-control methods. In this age group, 79 H. influenzae type b cases were identified by overlapping surveillance methods, and 221 random controls were selected by random digit dialing. Cases and controls were similar in sex, prior health, proportion attending day care, parental educational level, history of breast feeding, and proportion vaccinated with measles/mumps/rubella vaccine. The effect of H. influenzae type b vaccination was controlled in all analyses, and results of vaccine efficacy have been reported elsewhere. Cases were more likely to have a significant underlying medical condition, reside in home with more than six residents, have a lower yearly household income, have two or more smokers in the home, and to be black. Using conditional logistic regression models, the following were significant independent risk factors after adjusting for age, month of diagnosis, H. influenzae type b vaccine status, and the other factors: 1) more than two smokers in the house (odds ratio (OR) = 6.00; 95% confidence interval (CI) 1.49-24.06); 2) household size of more than six persons (OR for more than six vs. less than three persons = 3.71; 95% CI 1.10-12.60); and 3) black maternal race (OR for black vs. Hispanic = 3.47; 95% CI 1.41-8.53). We conclude that exposure to smoking in the home, living in households with more than six members, and the black race are each independently associated with an increased risk for H. influenzae type b disease in Los Angeles County children and, when combined, constitute a major reason for H. influenzae type b disease occurrence.