TOXICITY OF DMSO
The potentially toxic effects ofDMSO is the subject which virtually brought clinical investigations of DMSO to a standstill, but it is interesting to note that DMSO is of such low toxicity that grams per kilogram are used to
measure toxicity instead of milligrams per kilogram as in the case of most other drugs. The toxic effects of DMSO vary with concentration, dosage, and route of administration.
Common complaints associated with the use of DMSO are the garlic-like breath odor, erythema, dryness, occasional pruritus associated with cutaneous administration, and diarrhea. In humans, headache,32 nausea, sedation, and less frequently, dizziness2s ,26 are reported and it is assumed that animals may
experience similar phenomena. U rea-modified DMSO moderates some of these side effects. Urea-modified DMSO consists of 60parts DMSO, 20-parts urea, and 20-parts water. 6 This formula decreases the garlic or
sulfur odor in the breath and the cutaneous irritation, pruritus and dryness. Since the potential for systemic toxicity is the greatest with intravenous administration of DMSO, the LD50 has been determined for
several species and are in the range of 2.58.9g/ kg body weight. 33 Symptoms at near lethaI doses were similar in all species investigated and include spontaneous motor activity, tremors, muscular weakness,' prostration, transient convulsions, dyspnea, pulmonary edema, and hemorrhage. 33 The oral LD50 of DMSO is higher than the intravenous LD50 and is approximately 109/kg body weight. 34
With intravenous administration of DMSO it was found that there is no increased toxicity with repeated daily dosing, assuming that the repeated daily does not exceed the single maximum tolerated dose. 35 Damage to blood vessels due to DMSO is directly proportional to the concentration of DMSO and the number of repeated injections. The concentration of DMSO administered intravenously should not exceed 50% or the injected vessel may be subject to intimal damage, fibrosis, perivascular inflammation, and/or intravascular thrombi. 3s However, no necrosis or sloughing of the blood vessel occurs. At or above the maximum tolerated dose there is a transient increase in respiratory rate, an increase in diuresis, and evidence of hemoglobinuria and bilirubinuria which are a direct result of erythrocyte damage and subsequent release of hemoglobin. 35
Rapid in travenous administration of DMSO can induce seizures. 21 Local tissue reactions to subcutaneous or intramuscular injections are directly related to the concentration and total amount of DMSO injected. Reported responses to these injections include inf1~mmatory, hemorrhagic, gelatinous, and edematous tissue reactions, but there is no abscess formation, necrosis, or sloughing. 35 Intradermal injections of undiluted DMSO cause an intense local vasoconstriction followed by hemorrhage and necrosis,35 and therefore, should be avoided.
Most biochemical changes associated with the administration of DMSO are related to the damage incurred by the red blood cells. 35,36 This direct hemolytic effect is doserelated and is seen with intravenous DMSO
in high concentration or high dosage rate. Very high doses of oral DMSO cause hemorrhagic gastroenteropathy. Hemolysis results in a reversible anemia with a reduction in hemoglobin in the circulating blood, hemoglobinuria, hematuria, and bilirubinuria. As a result of red blood cell damage, reticulocytosis and increased erythroid activity in the spleen and bone marrow are often observed.
In spite of the dose-related hemolysis and subsequent hemoglobinuria associated with high concentrations of intravenous DMSO, there is no decrease in renal function and in general, no evidence of renal structural
changes. 36 Some reports indicate the presence of a mild tubular nephrosis,33 but there are no reports of nephrotoxic tubular damage. Also, there are no urine sediment abnormalities, and no increases in urine protein or glucose.
Liver damage with high doses of DMSO consists of fatty degeneration, cloudy swelling, granulation of parenchymal cytoplasm, and inflammation in the portal spaces. 33.35 Other changes include hemolyzed red blood cells in the hepatic sinusoids, cytoplasmic fragmentation of the Kupffer cells, and hemosiderin
granules in the interstitium.
Pulmonary changes associated with the conventional administration of DMSO are not common but with near-lethal doses of DMSO, development of pulmonary edema can occur. 35 The pathogenesis of pulmonary
edema is related to a decreased heart rate and blood pressure, vascular distention, and stasis of blood.
Teratogenic effects of DMSO appear to be n1inimal unless extraordinarily high doses of DMSO are administered. The most definite teratogenic effects are seen in the hamster and the chicken. 35 In the hamster, the teratogenicity of DMSO is directly related to the stage of development of the embryo when DMSO is
administered. Direct injection of DMSO into the chick embryo results in fetal abnormalities, but injection of DMSO into the yolk sac does not produce any teratogenic effect. Rabbits treated with very high doses of DMSO
demonstrate a reduction in embryo viability. 35
Administration of DMSO in high doses, to both male and female rats prior to mating, does not cause any reduction in fertility nor is it associated with any teratogenic effects. 33 The major concern associated with administration of DMSO to gravid animals is the dosage given, but it is unlikely in a clinical situation
that such high doses would be dispensed. The topical route of application of DMSO appears to be the least toxic. The most important aspect of the cutaneous toxicity ofDMSO involves local tissue reactions. DMSO passes
through the skin fairly rapidly and causes vasodilation and erythema proportional to the concentration of DMSO applied. Cutaneous application of high concentrations of DMSO slutions exaggerate the hydroscopic effects of DMSO, depriving the tissues of water. 33 Dogs and monkeys treated vvith 90% Dl\1S0 over
an extended period exhibit a slight hyperkeratosis of the skin with no other significant histological
changes in the skin. 35 In humans, 80% DMSO applied topically results in a significant incidence of eosinophilia, attributed to the cutaneous histamine-releasing effect of DMSO.33 Cutaneous administration of DMSO with occulusive bandages may cause a papillovesicular reaction which leads to inflammation and epidermal death. 37 Although these are not permanent changes, occulusive bandaging
should be avoided when using topical DMSO.
The transport and penetrant properties of DMSO impose a hazard to the cutaneous administration of DMSO. DMSO has the capability to enhance the absorption of topical medications and other materials into the skin,
and therefore, any other medication or compound present on the skin should be removed prior to cutaneous application of DMSO. DMSO and its metabolites will not accumulate in the tissues, and no delayed toxicity
to DMSO has been reported. 35 In animals treated with intradermal DMSO for 3 weeks, no signs of sensitization were noted when challenged with an intradermal dose of DMSO.35 Therefore, any toxic effects of DMSO will most likely be observed during or immediately following DMSO therapy.
Administration of DMSO causes the cortical fibers of the lens of the eye to become less relucent than normal and this change results in the production of a refractive error and myopia. 34 The severity of this change is directly related to the length of administration of DMSO and the concentration of DMSO
used. Clinically, severely affected animals have an opalescence in the center of the lens although the lens remains optically clear. The pathogenesis of the DMSO-induced lenticular change is not known. DMSO does not accumulate in the lens but following chronic administration, DMSO can be found in the cornea,
aqueous humor, and vitreous body. 33 These lenticular changes, once established, persist for long periods of time. In summary it is apparent that the toxicity of DMSO is minimal when used in clinically normal doses and concentrations. The toxic 93 !effects are most frequently seen in abnormally Ihigh experimental doses and concentrations.