Information Technology Measurement and Testing Activities at NIST.

Our high technology society continues to rely more and more upon sophisticated measurements, technical standards, and associated testing activities. This was true for the industrial society of the 20th century and remains true for the information society of the 21st century. Over the last half of the 20th century, information technology (IT) has been a powerful agent of change in almost every sector of the economy. The complexity and rapidly changing nature of IT have presented unique technical challenges to the National Institute of Standards and Technology (NIST) and to the scientific measurement community in developing a sound measurement and testing infrastructure for IT. This measurement and testing infrastructure for the important non-physical and non-chemical properties associated with complex IT systems is still in an early stage of development. This paper explains key terms and concepts of IT metrology, briefly reviews the history of the National Bureau of Standards/National Institute of Standards and Technology (NBS/NIST) in the field of IT, and reviews NIST's current capabilities and work in measurement and testing for IT. It concludes with a look at what is likely to occur in the field of IT over the next ten years and what metrology roles NIST is likely to play.

Disease-causing effects of environmental chemicals.

Both toxicologic studies and studies in environmental chemistry are important in assessing the potential adverse health effects of human exposures to hazardous environmental agents. This article discusses the toxic effects of chemical concentration at the target organ or site and how the concentration is related to the level of external exposure.

The impact of toxicity on carcinogenicity studies: implications for risk assessment.

This paper explores the inter-relationship between toxicity, genotoxicity, and carcinogenicity in laboratory rodents. To our knowledge this is the first attempt to integrate these factors and evaluate their implications for the process of risk assessment. The evaluation is based on information obtained from 2-year laboratory-animal studies involving 99 chemicals. The data suggest that only seven of the 53 positive carcinogenicity studies exhibited the types of target organ toxicity that could have been the cause of all observed carcinogenic effects. Furthermore, no apparent difference in mutagenicity as measured by the Ames Salmonella assay was observed between 'high dose only' carcinogens and the entire set of carcinogens. These findings suggest that the number of chemical carcinogens that we can identify solely through rodent studies as being potential tumor inducers through some indirect mechanism is small. Generally speaking, the identification of histopathological effects is not sufficient in itself for justifying mechanistic assumptions, and supplemental biological information will be necessary to reach definitive conclusions.

The impact of litter effects on dose-response modeling in teratology.

The fitting of dose-response models to teratology data involving littermates in order to generate estimates of teratogenic risk is receiving increasing attention as a potential alternative to the "safety-factor" approach to risk estimation. In this paper, we utilize the beta-binomial distribution to introduce varying degrees of intralitter correlation, and, for purposes of illustration, consider a logistic dose-response model that describes the logit of risk as a straight-line function of ln(dose). The biases and (exact and asymptotic) variances of the maximum likelihood estimators of the intercept and slope are studied by simulation as a function of the intralitter correlation structure.

Extrapolation of animal carcinogenicity data: limitations and pitfalls.

Laboratory-generated animal bioassay data often serve as the basis for estimating potential human cancer risk. However, there is no single procedure that has been universally accepted as the method of choice for extrapolating experimentally observed results to the low exposure levels that are generally of public health concern. All of the models proposed to date suffer from various limitations. Therefore, the most prudent approach may be to rely primarily on the more conservative procedures such as linear extrapolation until a better understanding of the biological mechanisms underlying the process of carcinogenesis is attained. In addition to the choice of an extrapolation model, there are a variety of other factors, such as the incorporation of background cancer rates, the potential for synergistic reactions, differential pharmacokinetic effects and differences in exposure regimen, that can have a significant bearing on the extrapolation of animal carcinogenicity data to man.

Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES).

Prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, has been associated with a low incidence of vaginal adenocarcinoma as well as a variety of more numerous benign abnormalities in the reproductive tract of human beings and experimental animals. For the purpose of assessing the effects of prenatal exposure to DES on postnatal reproduction tract function, timed pregnant CD-1 mice were treated subcutaneously with doses of DES ranging from 0.01 to 100 microgram/kg/day on days 9 through 16 gestation. The fertility of the female offspring was determined postnatally by a repetitive forced breeding technique. The most striking effect observed was a dose-related decrease in reproductive capacity ranging from minimal subfertility at the lower DES doses to a high frequency of total sterility at the highest DES doses. Reduced reproductive capacity appeared to be a reflection of both a decrease in the total number of litters and smaller litter sizes. A major component of the sterility seen in those females given higher doses of DES was oviductal/ovarian, since the number of ova recovered from the oviductal ampullae after induced ovulation was less than 30% that of controls. In addition, structural abnormalities of the oviduct, uterus, cervix, and vagina were observed, and contributed to infertility. These data suggest that in utero exposure to DES results in permanent impairment of female mouse reproductive capacity. Recent reports of altered pregnancy outcomes in young women who were exposed in utero to DES demonstrate the clinical importance of the findings obtained in mice.

Association between chloroform levels in finished drinking water supplies and various site-specific cancer mortality rates.

This paper discusses some of the statistical and biological problems that are likely to be encountered when an indirect or ecological approach is used to assess the possible public health impact of general population exposures to environmental agents. For purposes of illustration, the potential association between various site-specific cancer mortality rates and chloroform levels in public drinking water supplies was considered. The analyses that were performed demonstrated that, for the data sets under consideration, there were some definite associations between chloroform levels and cancer mortality for specific sites such as the rectum-intestine and bladder. However, the marked extent to which these results were dependent on (1) the weighting scheme adopted in the analysis, (2) the presumed appropriateness of the data, and (3) the characteristics of the statistical model was also clearly illustrated. Because of these dependencies the quantitative, causal interpretation of results generated from an indirect study would appear to be a very tenuous and questionable practice in most instances.

Blood pressure and lead levels in children.

Blood lead and hypertension are associated in adults. We attempted to duplicate this finding in a presumably more susceptible group of children. Small but statistically significant negative corelations were found between blood pressure and lead levels in these children. This indicated to us that the proposed positive relationship did not exist, and that the failure to detect such a relationship was not due to small sample size.

Alternatives to Rothman's approach for assessing synergism (or antagonism) in cohort studies.

K.J. Rothman has explored in some detail the issue of assessing the potential presence of synergism (or antagonism) in data generated from either a cohort or a case-control study. Arguing that the "natural" scale for quantifying the joint effects of two or more factors acting in combination is the probability scale, he has proposed a procedure based on a ratio-type index for evaluating two-factor interaction in the presence of non-zero background effects. In this paper, the authors review the rationale underlying Rothman's approach for a cohort study. They then present what they maintain is a simpler and more appropriate test procedure (utilizing a linear contrast of the observed risks) for the additive approximation to his basic probabilistic model of "no interaction." A likelihood ratio test based on his original model is also proposed, as well as a closed form approximation to it. Finally, the assessment of interaction in cohort studies involving exposure factors measured at more than two levels is addressed.

Effects in rats and guinea pigs of short-term exposures to sulfuric acid mist, ozone, and their combination.

Ozone and the oxides of sulfur are common environmental pollutants. The acute pulmonary lesions caused by ozone and sulfuric acid mist in rats and guinea pigs have been characterized. Rats are not affected by sulfuric acid mist in concentrations up to 100 mg/m3 except for reduced body weight at the higher doses. A true alveolitis develops in guinea pigs exposed to more than 20 mg/m3 sulfuric acid mist. The ozone lesion is primarily confined to the terminal bronchioles and proximal alveoli. In combination studies with up to 2 ppm ozone and up to 10 mg/m3 sulfuric acid mist, the pulmonary lesion and lung/body weight data were essentially the same as in exposure to ozone alone, and the number of statistically significant synergistic effects in rats and guinea pigs was about what one would expect to observe by chance alone.

Selection of the experimental unit in teratology studies.

In teratology experiments the litter (pregnant female) rather than the fetus is advocated as being the proper experimental unit upon which to base the statistical analysis. It is pointed out that per litter tests, by being based on the average fetal response within a litter, do take the individual fetus into account. Actual experimental data are used to show that when litter effects are present a per fetus analysis is invalid and may seriously exaggerate the significance level. It is also shown that there appears to be little loss in sensitivity in performing per litter tests even in the unlikely event that there are no litter effects. Thus it certainly seems prudent to analyze teratology data with test procedures that treat the litter as the experimental unit.

Is methotrexate therapy for psoriasis carcinogenic? A modified retrospective-prospective analysis.

The use of methotrexate in psoriasis has recently been questioned because of possible carcinogenic potential. Two hundred twenty-four patients began methotrexate therapy during 1960 to 1965 at the Cleveland Clinic and at Duke University Medical Center. The incidence of malignant neoplasms and mortality has been studied in 205 of these 224 patients. Mortality increased with hepatic disease. No increased incidence of total internal malignancy was found, nor did any one type of neoplasm appear predominant.

Teratogenic evaluation of 2,4,5-T.

The herbicide 2,4,5-trichlorophenoxyacetic acid is teratogenic and fetocidal in two strains of mice when administered either subcutaneously or orally and in one strain of rats when administered orally. The incidences of both cystic kidney and cleft palate were increased in the C57BL/6 mice as well as the incidence of cleft palate in the AKR mice. The incidence of cystic kidney was also increased in the rats. In addition, an increase in the ratio of liver weight to body weight in the mouse fetus and the occurrence of hemorrhagic gastrointestinal tract in the rat fetus suggest that this compound also has fetotoxic properties.