Observable tumours, risk assessment and experimental design.

The first goal of this article is to outline a design for an efficient experiment for testing each of many chemicals for carcinogenic potential by dermal exposure, including a risk assessment when appropriate. The second is to validate a general mathematical model for the dose-response function in this situation by using the results from a large experiment in skin painting done by the Oak Ridge National Laboratory. These two goals are related because the general model is used as a guide in the choice of an efficient design for testing the many chemicals on which information is required.

A cancer risk assessment for saccharin.

The results from a recently completed large experiment with rats exposed to saccharin show that the dose-response function is much steeper than was previously assumed. Based on this observed steepness, any implied cancer risk at the low doses of interest to man is very small.

Evaluation of the dose response and in utero exposure to saccharin in the rat.

A two-generation bioassay on sodium saccharin (NaS), involving 2500 second-generation male rats, was designed to determine the dose response for urinary bladder tumours in male rats and to evaluate other changes possibly related to the occurrence of the tumours. Six treatment groups (125-700 rats/group) were fed dietary levels of NaS ranging from 1.0 to 7.5%. To evaluate the role of in utero exposure, two additional groups were exposed to NaS either only during gestation via dams fed diet containing 5.0% NaS or for a single generation beginning at birth. In the latter group, the nursing dams were placed on an NaS diet immediately after giving birth and their offspring were weaned onto diets containing 5.0% NaS. A third additional group, included to evaluate the specificity of NaS and the role of excess sodium in the occurrence of urinary bladder tumours, was fed diet containing sodium hippurate (NaH) for two generations--5.0% NaH to the first generation and to the second until 8 wk old, and subsequently 3.0% because of unexpected toxicity. A clear dose response for urinary bladder tumours was observed in the second-generation NaS-treated male rats. The steep slope of the dose-response curve indicated a rapid decline in tumour incidence with decreasing dose. The 1.0% dietary level (fed to 700 rats) was considered to be a no-effect level for bladder tumours. The only other treatment-related pathological changes were an increase in urinary bladder weight in rats fed greater than or equal to 3.0% and an increase in mineralization of the kidneys with greater than or equal to 1.0%. Several physiological effects were seen in the NaS-treated groups showing an increase in bladder tumours (i.e. those fed greater than or equal to 3.0%). Some changes, e.g. depressed growth and increased water consumption, were indicative of a general disturbance of these rats, but analysis of body-weight, food-consumption, compound-consumption and water-consumption data revealed no correlations within any dose group between these quantitative data and the occurrence of bladder tumours. Other changes indicative of the compromised situations of the rats fed high dietary levels of NaS were anaemia in weanling rats fed 5.0 or 7.5% and a reduction in litter size at dietary levels greater than or equal to 3.0%. Changes in urine volume and urine osmolality were highly correlated with the occurrence of the urinary bladder tumours.(ABSTRACT TRUNCATED AT 400 WORDS)

Microfluidic and transducer technologies for lab on a chip applications.

Point-of-care diagnostic devices typically require six distinct qualities: they must deliver at least the same sensitivity and selectivity, and for a cost per assay no greater than that of today's central lab technologies, deliver results in a short period of time (〈15 min at GP; 〈2h in hospital), be portable or at least small in scale, and require no or extremely little sample preparation. State-of-the-art devices deliver information of several markers in the same measurement.

Lindane bioassay studies and human cancer risk assessment.

Benzene hexachloride or hexachlorocyclohexane comes in eight isomeric forms which differ in the spatial positions of the chlorine atoms on the boat and chair forms. Only one, however, gamma-isomer (lindane) possesses relevant insecticidal activity. The majority of studies on the potential carcinogenicity of benzene hexachloride, however, did not discriminate between the various isomers because they assumed that carcinogenicity is independent of steric structure. Also, proper differentiation between morphologic endpoints was not duly carried out and considered. The present evaluation of lindane's biologic activity was restricted to the lifelong studies in which pure lindane (greater than 99.5%) was utilized and the morphology of the observed lesions, mainly in the liver, were classified according to their biologic behavior into hyperplastic, benign neoplastic, and malignant entities. None of the studies gave evidence that lindane was carcinogenic in mice and rats. An enhancement of benign liver tumors (tumorigenic effect) was observed only in CF1 male mice (17/56 at the only tested dose: 400 ppm vs. 3/89 observed in the nontreated controls). Dose-response function of this tumor response in conjunction with two other lifetime studies (80 and 160 ppm in B6C3F1 and 50, 25, and 12.5 ppm in NMRI mice) were best described by the Weibull model, giving a relatively high estimate of its shape parameter (m = 2.5). Assuming similar susceptibility of humans to lindane and considering maximal occupational exposure to this agent (professional applicators), the probability of lindane associated tumor development was estimated as 2.2 X 10(-10). Because this cancer risk is five orders of magnitude below the acceptable health risk, this evaluation concludes that environmental exposure to lindane does not pose a threat to human health.