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HEXACHLOROPHANE TOXICITY IN SHEEP
1251 Is it fanciful to suppose that excessive pancreatic stimulation in infancy might predispose to later diabetes ? 7 Portesbery Road, Camberley, Surrey.
A. M. W. PORTER.
HEXACHLOROPHANE TOXICITY IN SHEEP SIR,—Hexacblorophane (H.c.P.) has been widely used
as
bacteriocide in medical soaps, powders, creams, and cosmetic preparations, but the safety of its use in some of these preparations has been questioned.In veterinary medicine a single oral dose of this compound is an effective anthelmintic against liver flukes (Fasciola hepatica) in sheep and cattle.22 Recent studies of the toxicity of H.c.P. in rats and monkeys haveshown that prolonged exposure affects the central nervous system (c.N.S.).3,4 We wish to report the occurrence of status spongiosus in the c.N.s. of sheep after short periods of oral dosing with the compound. a
CLINICAL
AND
HISTOPATHOLOGICAL EFFECTS OF DAILY ADMINISTRATION OF HEXACHLOROPHANE TO SHEEP
in any of the three sheep which had received only one dose. The severity of the histological lesions varied with the number of doses, but the occurrence of clinical abnormalities was not related to the severity of the lesions. The results of these experiments show that lesions appear in the c.N.s. much earlier than was shown in previous studies with rats.3 In rats a daily intake of 25 mg. H.c.p. per kg. per day for 2 weeks resulted in weakness of the hindquarters which progressed to posterior paralysis after 3-5 weeks, and histological examination of the C.N.s. after 14 weeks revealed status spongiosus of the white matter. Status spongiosus has also been described in monkeys washed daily from birth to 90 days in a 3% emulsion of H.C.p.4 but daily oral dosing of young adult monkeys for 28 days at rates up to 15 mg. per kg. did not produce brain lesions.5 Our observation that five out of six sheep, which had received 12 doses of H.c.p. and had developed severe lesions, were clinically normal could be relevant to situations in babies which might also develop lesions in the absence of clinical signs. These findings reinforce previous warnings against the indiscriminate use of, and prolonged exposure to, H.C.P. in human and veterinary medicine. Agricultural Research Council Institute for Research Animal Diseases,
Compton,
near
on
Newbury,
Berks.
GRAHAM A. HALL IAN M. REID.
HEXACHLOROPHANE TERATOGENICITY IN RATS
SiR,-Dr. Gaya (Oct. 14, p. 821) brought to our attention important point about the interaction of hexachlorophane (H.C.P.) and non-ionic wetting agents, such as’Tween 80’, on bacterial viability. However, the inhibition of antibacteriostatic effects of H.C.P. by tween 80 may be quite different from the effects of tween 80, if any, on the toxicity of H.c.P. Gump,6 in his review of the toxicity of H.C.P., cited studies carried out by Leberco Laboratories in which the oral toxicity of H.C.P. was tested in mice with and without addition of tween 80. A dose of 250 mg. per kg. H.C.P. produced 100% mortality and this effect did not change when 1 part of H.C.P. was mixed with as much as 2, 4, and 9 parts tween 80. Since the symptoms produced in our animals after vaginal treatment were very similar to those after oral ingestion, we are confident that the toxic maternal effects are due to H.C.P. In addition, recent preliminary studies (unpublished) in our laboratory, where H.c.P. was dissolved in ethyl alcohol, have shown maternal toxicity and teratogenicity to be very similar to those we an
* Dose rate 20 mg. per kg. t 24 hours after last dose.
body-weight.
Three experiments were performed using female and castrated male yearling sheep which were of the Herdwick breed in experiments 1 and 2 and Suffolk x Clun Forest animals in experiment 3. In all experiments a 5% (w/v) suspension of H.c.p. in liquid paraffin was administered at the rate of 20 mg. per kg. body-weight; control sheep received liquid paraffin. The dose-rate used was selected to be similar to that which had produced lesions in the C.N.S. of rats 3 and also because an effective single oral dose of H.c.r. for the treatment of fascioliasis in sheep is 10-20 mg. per kg.2 The suspension was given orally in experiments 1 and 2 and was injected directly into the rumen in experiment 3. The sheep were dosed at the same time each morning and were killed, by exsanguination after electrical stunning, 24 hours after the last dose. From each animal, brain, spinal cord, and a range of other tissues were fixed by immersion in 12% neutral buffered formalin. The results are summarised in the accompanying table. The clinical effects of H.C.P. varied from death after two doses in one sheep to apparent normality after twelve doses in five sheep. Status spongiosus of the white matter of the brain and spinal cord was seen in every sheep which had received two or more doses, but it was not detected 1. Br. med. J. 1972, i, 705. 2. Bosman, C. J., Thorold, P. Ass. 1961, 32, 227.
3. 4.
W., Purchase,
H.
S. J. S. Afr.
vet.
described (Oct. 7, p. 765) with tween 80. Furthermore, observed no gram-positive bacteria but a true increase in gram-negative bacteria associated with maternal vaginal infections which would indicate the antibacterial activity of H.C.P. in our animals. The large proportion of H.C.P. in relation to tween 80 (45/1) in our suspension would suggest that the synergistic effects of tween 80 on H.C.P. toxicity were minimal if any. In fact, if tween 80 were inhibiting the toxic action of H.c.P. to any significant extent, the teratogenic effects of H.C.P. might be produced with levels similar to those in products we
for
use
in
man.
Department of Anatomy, Harvard Medical School, Boston, Massachusetts 02115. Environmental Toxicology Research Laboratory, Environmental Protection
med.
Kimbrough, R. D., Gaines, T. B. Archs envir. Hlth, 1971, 23, 114. Hart, E. R. Bionetics Research Laboratories Inc., Nov. 11, 1971. Cited by Lockhart, J. D. Pediatrics, 1972, 50, 229.
Cincinnati,
Agency, Ohio 45237, U.S.A.
CAROLE A. KIMMEL.
WELLINGTON MOORE, JERRY F. STARA.
5. Santolucito, J. A. Tox. appl. Pharmac. 1972, 22, 276. 6. Gump, W. S. J. Soc. cosmet. Chem. 1969, 20, 173.
JR.
A. M. W. PORTER.
HEXACHLOROPHANE TOXICITY IN SHEEP SIR,—Hexacblorophane (H.c.P.) has been widely used
as
bacteriocide in medical soaps, powders, creams, and cosmetic preparations, but the safety of its use in some of these preparations has been questioned.In veterinary medicine a single oral dose of this compound is an effective anthelmintic against liver flukes (Fasciola hepatica) in sheep and cattle.22 Recent studies of the toxicity of H.c.P. in rats and monkeys haveshown that prolonged exposure affects the central nervous system (c.N.S.).3,4 We wish to report the occurrence of status spongiosus in the c.N.s. of sheep after short periods of oral dosing with the compound. a
CLINICAL
AND
HISTOPATHOLOGICAL EFFECTS OF DAILY ADMINISTRATION OF HEXACHLOROPHANE TO SHEEP
in any of the three sheep which had received only one dose. The severity of the histological lesions varied with the number of doses, but the occurrence of clinical abnormalities was not related to the severity of the lesions. The results of these experiments show that lesions appear in the c.N.s. much earlier than was shown in previous studies with rats.3 In rats a daily intake of 25 mg. H.c.p. per kg. per day for 2 weeks resulted in weakness of the hindquarters which progressed to posterior paralysis after 3-5 weeks, and histological examination of the C.N.s. after 14 weeks revealed status spongiosus of the white matter. Status spongiosus has also been described in monkeys washed daily from birth to 90 days in a 3% emulsion of H.C.p.4 but daily oral dosing of young adult monkeys for 28 days at rates up to 15 mg. per kg. did not produce brain lesions.5 Our observation that five out of six sheep, which had received 12 doses of H.c.p. and had developed severe lesions, were clinically normal could be relevant to situations in babies which might also develop lesions in the absence of clinical signs. These findings reinforce previous warnings against the indiscriminate use of, and prolonged exposure to, H.C.P. in human and veterinary medicine. Agricultural Research Council Institute for Research Animal Diseases,
Compton,
near
on
Newbury,
Berks.
GRAHAM A. HALL IAN M. REID.
HEXACHLOROPHANE TERATOGENICITY IN RATS
SiR,-Dr. Gaya (Oct. 14, p. 821) brought to our attention important point about the interaction of hexachlorophane (H.C.P.) and non-ionic wetting agents, such as’Tween 80’, on bacterial viability. However, the inhibition of antibacteriostatic effects of H.C.P. by tween 80 may be quite different from the effects of tween 80, if any, on the toxicity of H.c.P. Gump,6 in his review of the toxicity of H.C.P., cited studies carried out by Leberco Laboratories in which the oral toxicity of H.C.P. was tested in mice with and without addition of tween 80. A dose of 250 mg. per kg. H.C.P. produced 100% mortality and this effect did not change when 1 part of H.C.P. was mixed with as much as 2, 4, and 9 parts tween 80. Since the symptoms produced in our animals after vaginal treatment were very similar to those after oral ingestion, we are confident that the toxic maternal effects are due to H.C.P. In addition, recent preliminary studies (unpublished) in our laboratory, where H.c.P. was dissolved in ethyl alcohol, have shown maternal toxicity and teratogenicity to be very similar to those we an
* Dose rate 20 mg. per kg. t 24 hours after last dose.
body-weight.
Three experiments were performed using female and castrated male yearling sheep which were of the Herdwick breed in experiments 1 and 2 and Suffolk x Clun Forest animals in experiment 3. In all experiments a 5% (w/v) suspension of H.c.p. in liquid paraffin was administered at the rate of 20 mg. per kg. body-weight; control sheep received liquid paraffin. The dose-rate used was selected to be similar to that which had produced lesions in the C.N.S. of rats 3 and also because an effective single oral dose of H.c.r. for the treatment of fascioliasis in sheep is 10-20 mg. per kg.2 The suspension was given orally in experiments 1 and 2 and was injected directly into the rumen in experiment 3. The sheep were dosed at the same time each morning and were killed, by exsanguination after electrical stunning, 24 hours after the last dose. From each animal, brain, spinal cord, and a range of other tissues were fixed by immersion in 12% neutral buffered formalin. The results are summarised in the accompanying table. The clinical effects of H.C.P. varied from death after two doses in one sheep to apparent normality after twelve doses in five sheep. Status spongiosus of the white matter of the brain and spinal cord was seen in every sheep which had received two or more doses, but it was not detected 1. Br. med. J. 1972, i, 705. 2. Bosman, C. J., Thorold, P. Ass. 1961, 32, 227.
3. 4.
W., Purchase,
H.
S. J. S. Afr.
vet.
described (Oct. 7, p. 765) with tween 80. Furthermore, observed no gram-positive bacteria but a true increase in gram-negative bacteria associated with maternal vaginal infections which would indicate the antibacterial activity of H.C.P. in our animals. The large proportion of H.C.P. in relation to tween 80 (45/1) in our suspension would suggest that the synergistic effects of tween 80 on H.C.P. toxicity were minimal if any. In fact, if tween 80 were inhibiting the toxic action of H.c.P. to any significant extent, the teratogenic effects of H.C.P. might be produced with levels similar to those in products we
for
use
in
man.
Department of Anatomy, Harvard Medical School, Boston, Massachusetts 02115. Environmental Toxicology Research Laboratory, Environmental Protection
med.
Kimbrough, R. D., Gaines, T. B. Archs envir. Hlth, 1971, 23, 114. Hart, E. R. Bionetics Research Laboratories Inc., Nov. 11, 1971. Cited by Lockhart, J. D. Pediatrics, 1972, 50, 229.
Cincinnati,
Agency, Ohio 45237, U.S.A.
CAROLE A. KIMMEL.
WELLINGTON MOORE, JERRY F. STARA.
5. Santolucito, J. A. Tox. appl. Pharmac. 1972, 22, 276. 6. Gump, W. S. J. Soc. cosmet. Chem. 1969, 20, 173.
JR.