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A testing procedure is described for the assessment of the toxicological response (e.g., acute toxicity or mutagenicity) of any combination and number of chemical, physical, and biological agents, with no more effort for a particular combination than for a single agent. The method provides a simple, sensitive, and quantitative index of synergism, antagonism, and additivity, and it has been demonstrated experimentally in rats by determining the acute lethality of combinations of cadmium, mercury, and lead salts. In a combination of two metal salts, the dose of one metal of the pair was fixed at or near the no-effect level while the dose of the second metal was increased until the entire dose-response curve was obtained. To evaluate interactions of the three metals, the previous pair of metals were kept fixed at their combined extrapolated LD1 level, and the third metal was increased. The statistical treatment of the data employed a computer program that did not involve probit transformations, but rather the approximate linear relationship between the fractional response and the logarithm of the dose. A particular combination could be synergistic, antagonistic, or additive, depending on the relative doses employed. Generally, a combination was synergistic when the most toxic member was present at or near its LD1 dose in the presence of the much less toxic member; the same combination was protective when the least toxic member was present at or near its LD1 dose. The results clarify apparently contradictory reports regarding the biological effects of metal combinations. The application of the testing procedure to combinations of mutagens is described, and an example is cited involving, for a particular bacterial mutagen, a combination of N-methyl-N'-nitro-N-nitrosoguanidine with ethylmethanesulfonate.

The fate of 2,4-dinitrochlorobenzene, a potent contact sensitizing chemical, and 2,4-dichloronitrobenzene, a non-sensitizer, was compared following their application to the skin of BALB/c mice. Although both chemicals were able to bind to protein in vitro and were capable of being absorbed across mouse skin in vivo, only 2,4-dinitrochlorobenzene was able to bind to cells in the skin and to induce the movement of these cells from the epidermis into the dermis and ultimately into the draining lymph nodes. The sensitization potential of a chemical may therefore be dependent on its ability to associate with and stimulate the efflux of cutaneous antigen-presenting cells.

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Whether or not pressor responsiveness changes in unanesthetized rats during recurrent sympathetic excitation was determined by recording blood pressure and heart rate continuously while the posterior hypothalamus was stimulated repeatedly with constant currents. Because preliminary tests showed that telestimulation with a radio-controlled stimulator produced erratic responses, awake rats were routinely stimulated in a conventional manner by connecting them through wires to a square-wave stimulator. Although tachycardia was the most common chronotropic effect, bradycardia also occurred, and both responses were occasionally seen in the same rat at different times. Inhibition of chronotropic responses by combined pharmacologic blockage with propranolol and atropine did not affect corresponding pressure responses in normotensive rats. Renal and spontaneously hypertensive rats always had larger pressor responses than normotensive ones, and, in spite of individual variations, responsiveness generally remained unaltered during 3-6 h of repeated hypothalamic stimulation. These results indicate that in awake normotensive or hypertensive rats cardiovascular responses to posterior hypothalamic stimulation continue unabated even when stimulation is repeated for hours.

SUMMARY Hypertension was induced experimentally by subjecting rats to vigorous shaking, 4 hours (at random) daily for 14 weeks. Systolic pressures measured with the tail-cuff method began to rise after the first week and were significantly derated on Weeks 3, 4, 6, 7, and 8, but reverted to normotensive levels thereafter despite continued shaking. A similar hypertension was then induced in another group of rats and when spontaneous remission occurred, pressor responsiveness was tested on the eleventh week by recording aortic pressures from indwelling catheters. Pressor responses to further shaking or electrical stimulation of the anterior hypothalamus were smaller in shaker-stressed than in control rats, while those to injected norepinephrlne were almost the same in both groups. Spike potentials recorded from postganglionlc sympathetic (splanchnic) nerves showed higher baselines but smaller increases in neural firing during hypothalamic stimulation in shaker-stressed than in control rats. These results suggest that while shaker stress alone can induce hypertension, the resulting blood pressure elevation is not sustained, perhaps because adaptation within the central nervous system concurrently reduces pressor responsiveness. action to stress, and based on the assumption that with frequent repetition the pressure elevation eventually becomes sustained, chronic exposure to stress has often been used for inducing experimental hypertension. Air blasts, 1 intermittent decompression, 2 aversive operant conditioning,' psychosocial stimuli, 4 and a mixture of shaking, noise, and flashing lights," have all been found effective in making rats hypertensive. Because the hypertension thus induced can be prevented by chemical sympathectomy with 6-hydroxydopaminc" or by doses of amethyl tyrosine that deplete brain catecholamines selectively, 7 the involvement of central sympathetic mechanisms has been proposed. Chronic exposure to noise and flashing lights requires a precisely controlled laboratory environment that is more elaborate and expensive to set up than one based on shaking alone. Whether shaking (henceforth referred to as shaker 311 stress), which is more potent than either noise or flashing light in eliciting pressor or tachycardiac effects," can induce hypertension when applied alone is unknown. While attempting to resolve this question, we found the resulting blood pressure elevation unsustained. Consequently, additional experiments were done to determine whether pressor and neural responses to hypothalamic stimulation had been altered by previous exposure to shaker stress.Methods Two groups of 7-week-old female rats of the Sprague-Dawley strain, were purchased from Hilltop Laboratory Animals, Inc. (Chatsworth, CA) and randomly divided into control and experimental subgroups. Of 18 rats in the first group, half were used as controls and the others exposed to shaker stress manipulation for 14 weeks while systolic pressures, heart rates, and body weights were measured once weekly. A second group of 24 rats (12 contro...