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Although hexavalent chromium, Cr(VI), is a potent sensitizer and inducer of allergic contact dermatitis and is found in many common materials, no standard or guideline currently exists for protection against these effects in environmental exposure. There appears to be a generalized allergenic potential among the various compounds of Cr(VI). Estimates of the prevalence of Cr sensitivity in the population are uncertain, but range from about 2% of the total population in Finland to as high as 20% in U.S. populations with a dermatitis. Based on the thresholds reported for nine separate patch-test studies and statistical analysis of the aggregate dose-response relationship from 72 separate observations from these studies and on studies of allergic responses to bleaches and detergents, the effective threshold for elicitation of allergic contact dermatitis in sensitized populations is about 10 ppm (mg/L) Cr(VI) (as chromium) in solution. Based on evaluation of the literature on cement dermatitis, the threshold concentration of extractable Cr(VI) in solid material may be as low as 10 ppm (microgram/g). For ingestion of Cr(VI), the lowest observed effect level (LOEL) dose for elicitation is 0.26 microgram/kg. In calculating the threshold concentration of Cr(VI) in soil for elicitation of contact dermatitis, extractability must be taken into account.

Predictive tests are of value in forecasting the response of a population to a sensitizer; diagnostic testing is used to determine what substances may actually be producing dermatologic problems. Skin sensitization predictive and diagnostic data for the eleven most frequently encountered skin sensitizers in Western Europe, Canada and the United States are reviewed. These compounds include two drugs (benzocaine and neomycin), two cosmetic ingredients (p-phenylenediamine and balsam of Peru), four preservatives (formaldehyde, ethylenediamine, parabens and mercurials) and three ingredients of wearing apparel (nickel, chromium and thiram). Many of the data were collected by the North American Contact Dermatitis Group and the International Contact Dermatitis Research Group on tests with 1,200 and 4,825 dermatologic patients, respectively; the remainder were obtained by individual investigators with smaller groups of subjects. The data obtained by various investigators are discussed in relation to the factors which affect the extent and degree of sensitization which they can cause.

Hairless mice were administered various amounts of 8-methoxypsoralen (8-MOP) by gavage, followed by irradiation with ultraviolet light (UVA) two or more times per week for periods ranging from 1 to 12 months. The minimum phototoxic dose was 20 mg/kg body weight by this route of administration and potential for serious organ toxicity in long-term exposures was investigated. No histologic features of cutaneous malignancy were encountered under test conditions which produced prolonged phototoxicity, deep ulceration, cicatrization, and other deformities. Repeated daily gavaged doses of 20 mg psoralen/kg body weight in conjunction with twice weekly irradiation for 10 min with UVA elicited an erythematous phototoxic reaction, but did not give rise to subsequent skin lesions. 8-MOP in repeated daily gavage doses of 30 mg and 40 mg/kg body weight combined with twice weekly UVA irradiation for 10 min caused severe burning with subsequent scarring, but did not induce malignant tumors in experiments lasting lasting 8 months. No organ toxicity was seen except for toxic liver changes when severe cutaneous burn and pronounced ulcerations were produced. Limited immunologic studies disclosed no abnormalities in this system.

To estimate the influence of topical treatment with DMBA and induced tumors on delayed hypersensitivity, the response of spleen lymphocytes to PHA in vitro and macrophage migration inhibition with PHA were studied in DMBA-treated hairless mice. DNA synthesis and blastic transformation of cultured lymphocytes decreased after 6-12 weeks of DMBA application. Lymphocyte response to PHA gradually diminished during the experiment, as compared with control animals. Since the malignant transformation of skin tumors was not observed before 16 weeks of DMBA carcinogenesis, it seems that derangements in cellular immunity preceded the malignant proliferation. The increase in spleen weight and the absence of PHA-induced inhibition of macrophage migration in hairless mice with malignant tumors may also be related to the influence of the tumor itself on the lymphatic system of experimental animals.

A study was made to evaluate the effects of vehicle and challenge concentration on response of human subjects to potential allergens. In the vehicle studies the modified Draize test was used to test the response of subjects to cinnamic aldehyde and to costus oil, administered at two skin sites, in petrolatum and in 95% ethyl alcohol. In two tests of costus oil, alcohol proved to be more effective in eliciting a response than petrolatum; on the other hand, in one test with cinnamic aldehyde, no difference in results was obtained with these two vehicles. In the concentration studies, subjects known to be sensitive to the test substance were tested by the Al test with costus oil (three concentrations), chloracetamide (four concentrations), or thimerosal (three concentrations); petrolatum was used as the vehicle in each case. Results of the vehicle test showed no compelling reason for the selection of one vehicle rather than another. Results of the concentration tests indicated that concentration does have an effect on the intensity and frequency of reactions to potential allergens.

Two experiments were conducted. In the first, 9 adult male subjects applied a marketed hair dye containing 2% lead acetate according to prescribed directions daily for a period of 90 days. Scalp, axillary and pubic hair were monitored for lead content before and at the end of the test period. Scalp hair analyses were used to confirm application of the hair dye; axillary and pubic hair were analyzed as biologic indicators of systemic lead absorption, i.e., metabolic incorporation of lead in hair growing at sites different from the dyed site. The axillary and pubic hair lead levels ranged from less than 6 to 41 ppm at the start and rose to 27 to 466 ppm at the conclusion of the experiment. Using 80 ppm hair lead as a measure of significant systemic absorption, 7 of 9 subjects showed this effect according to uptake by axillary hair and 4 of 9 according to pubic hair uptake. In the second experiment, blood and hair lead levels and blood erythroporphyrin were measured in 11 children from a pica clinic. Blood lead and hair lead levels were significantly correlated, i.e., r = +0.84. A regression formula was constructed relating these two parameters and blood lead values were predicted for the data of experiment 1, using observed hair lead values. The technique has important limitations; nevertheless, within these limitations, 1 of 9 subjects might be expected to have sustained an elevated blood lead level, i.e., in excess of 50 microgram/100 ml. It therefore appears that in the use of lead acetate hair dyes, some lead is absorbed systemically from the scalp.

Research with phototoxic agents relevant to man has been usually related to their clinical toxicity potential (bergamot dermatitis) or attempts to harness their toxic properties for the therapy of vitiligo and psoriasis. This review is concerned mainly with the former. Our insights are related mainly to information gained from bergamot, an obvious form of clinical toxicity that long awaited simply animal or human models for experimental study. Are there other forms of phototoxicity that are less obvious? Are any melanodermas or chloasmas due to phototoxicity originating from undelineated chemicals? Will other forms of clothing dermatitis (such as bikini dermatitis) be demonstrated as being caused by phototoxic agents? Those questions should be answered by the alert investigator. The experimental tools are available and await the use of the inquisitive mind.

This article reviews local and systemic effects which relate to hair dye formulation and hair dye ingredient tests and experiences in man and animals. Mutagenic and carcinogenic aspects are discussed. In a very limited way, safety and hazards of using hair dyes are interpreted for consumers.

Further confirmation of the effects of vehicles and elicitation concentration in experimental contact sensitization testing with fragrance ingredients is reported. A dose-response relation was seen when sensitized human subjects were challenged with dihydrocoumarin, alantroot oil and diethylmalleate. Furthermore, alcohol was shown to be a more effective vehicle than petrolatum, when cinnamon bark oil, vetiver acetate and diethylmalleate were used in predictive tests. The relation of these findings to risk-benefit judgments is discussed briefly.

1. It has been shown quantitatively that the degree of response of the hind limbs of tadpoles to the action of thyroxin is dependent upon the lengths of the limbs at the beginning of treatment. 2. Both the potency of the inducing substance and the rate of penetration of the substance into the animal might be involved in the effects of hydrogen ion concentration on induced development. 3. Changes in hydrogen ion concentration affect the inducing power of thyroxin and iodine differently. With thyroxin, it is the rate of penetration of the molecule which determines the amount of growth, but with iodine it is the chemical form in which the substance has entered the animal which is of prime importance. 4. The hydrogen ion concentration of thyroxin solutions does not affect their potency when they are injected into tadpoles. 5. Change in hydrogen ion concentration of the environment does not affect the potency of thyroxin injected into tadpoles. 6. When thyroxin is administered in the environmental solution its effects, as measured by increase in hind limb length are greater at higher than at lower hydrogen ion concentrations in the range tested. 7. Since the potency of thyroxin is unaffected by change in hydrogen ion concentration when the thyroxin solution is injected, the above fact (point 6) seems explicable only on the basis of differences in the rate of penetration of thyroxin into the animals at the different hydrogen ion concentrations. 8. These differences in penetration of the thyroxin at different hydrogen ion concentrations may be the result of a differential effect of hydrogen ion concentration upon the rate of metabolism of the animal. The metabolic rate is significantly greater when the tadpoles are kept in solutions of higher hydrogen ion concentration than when they are kept in solutions of low hydrogen ion concentration. It is postulated that the rate of metabolism, since it controls the rate of intake of the environmental fluid and therefore of dissolved thyroxin, also controls the amount of thyroxin-induced development. 9. Change in hydrogen ion concentration of iodine solutions affects their potency when injected into tadpoles. A peak of effectiveness is reached at about the neutral point, with a lowered efficiency as the hydrogen ion concentration is either increased or decreased from this point. 10. Change in hydrogen ion concentration of the environment affects the potency of iodine injected into tadpoles. The effect is similar to that noted in point 9. 11. The hydrogen ion concentration of the environment seems to affect the chemical nature of the iodine in solution in the environment. If this is so, it is possible that the differences in the metamorphic effects of iodine at different hydrogen ion concentrations are dependent upon the chemical form of iodine present. 12. The effect of hydrogen ion concentration on normal development is similar to that on thyroxin-induced development; an effect on the rate of metabolism of the animal causes increased growth in more acid solutions.