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Carbon DisulfideThe September 1998 issue of EHP con-tained two articles about the neurotoxicityof carbon disulfide. The "NIEHS News"article (1) reported on a collaborative studythat involved scientists from the NIEHS(Research Triangle Park, NC), the U.S.Environmental Protection Agency(Research Triangle Park, NC), theUniversity of North Carolina (Chapel Hill,NC), Duke University (Durham, NC), andVanderbilt University (Nashville, TN). Inthis study, the neurotoxicity of carbondisulfide was detailed from the earliest mol-ecular alterations to neurobehavioral find-ings to electrophysiologic and morphologicchanges, and the utility of intramolecularcross-linking in hemoglobin as a biomarkerwas defined. I was pleased to read thisreport, and even more pleased to have par-ticipated in this study, but I was distressedto see the cover story in the same issue.

"Multiple System Atrophy FollowingChronic Carbon Disulfide Exposure" (2),in the "Grand Rounds in EnvironmentalMedicine," is a case report of an individualwho developed a degenerative nervous sys-tem disease, olivopontocerebellar atrophy,and who had been chronically exposed tocarbon disulfide while working for 34 yearsin a viscose rayon plant in the UnitedStates. Frumkin (2) concluded, "While thisassociation has not previously been report-ed, it is clinically and pathologically consis-tent with a range of movement disordersseen in the setting of occupational carbondisulfide exposure."

Frumkin never saw this patient, norwas he consulted by the patient's physi-cians during the course of this disease; heonly reviewed the medical records anddiagnostic studies as an expert witness forthe plaintiff in a case that failed to con-vince a Texas jury that a cause-and-effectrelationship existed between carbon disul-fide exposure and this man's disease (3). Ialso reviewed this material and concludedthat such a relationship was not evenremotely plausible; indeed, I thought thatthere were excellent reasons to concludethat his disease bore no relationship to theexposure. Thus, the publication of thispaper raises several concerns: Why didFrumkin feel authorized to publish thisreport, and were the editors informedabout his relationship to this case? Was thepaper reviewed by experts in neurotoxicol-ogy, clinical neurology, and neuropatholo-gy? Will readers conclude that carbondisulfide causes multisystem atrophy? Howmany more lawsuits will be filed allegingthat since B followed A, A caused B, andhow many more physicians will reach thisvacuous conclusion?

The individual described in this paper(2) had classical olivopontocerebellaratrophy, beginning with cerebellar ataxiaand progressing over years to involve longtracks and cranial nerve nuclei in the pons.Neither the cerebellum nor the pontinenuclei are affected in carbon disulfide toxic-ity. However, Frumkin pointed out thatolivopontocerebellar atrophy is part of aspectrum of diseases termed multisystematrophy, which also includes striatonigraldegeneration, a disease characterized byclinical parkinsonism. Although extrapyra-midal involvement in carbon disulfide toxi-city has been alleged in the clinical literature(4-11), the only experimental studiesreporting lesions in the extrapyramidal sys-tem were published over 50 years ago andinvolved uncontrolled exposures to carbondisulfide that resulted in repeated apneicepisodes and confounding hypoxia (12-14).Extrapyramindal lesions have never beenobserved in modern experimental studies,nor did the patient in Frumkin's report (2)manifest extrapyramidal signs. On the otherhand, the most sensitive structure in thenervous system to carbon disulfide-induceddamage is the axon, and this patient neverdeveloped evidence for an axonopathy atany time during his career or during his ter-minal illness. Thus Frumkin's statementthat the patient's course of illness was clini-cally and pathologically consistent with car-bon disulfide toxicity has no basis in fact.

Although it certainly was impressive tosee an MRI scan on the cover of EHP, thispaper is not based in either strong scienceor competent clinical medicine. We dependupon physicians who practice occupationaland environmental medicine to apply thescience of toxicology to the evaluation andtreatment of patients who have beenexposed to toxicants. When the exposureinvolves an agent whose toxicity has neverbeen suspected, case reports have value inalerting physicians and the public to possi-ble dangers. Considerable caution must beexercised, however, in assigning cause-and-effect relationships between toxicants anddisease, especially when the agent in ques-tion has been in use for many decades, hasbeen studied extensively, and has been sub-jected to strict regulatory standards.

Doyle G. GrahamVanderbilt University Medical Center

Nashville, TennesseeE-mail: doyle.graham@mcmail.vanderbilt.edu

REFERENCES AND NOTES1. Manuel J. NIEHS News: Carbon disulfide neurotoxicity

defined. Environ Health Perspect 106:A428-A430 (19981.2. Frumkin H. Multiple system atrophy following chronic

carbon disulfide exposure. Environ Health Perspect106:611-613 (1998).

3. Charles S. Jones, individually and as representative ofthe heirs and estate of West Berry Becton, Sr. and MaryBecton v. Rhone-Poulenc, Inc., et al. Civil Action No. H-

96-1904. U.S. District Court for the Southern District ofTexas, Houston Division, 28 August 1998.

4. Seppalainen AM, Haltia M. Carbon disulfide. In:Expermental and Clinical Neurotoxicology (Spencer PS,Schaumburg HH, eds). Baltimore, MD:Williams &Wilkins, 1980;356-373.

5. Audo-Gianotti GB. Le Parkinsonisme-sulfo-carboneprofessionel. Presse Med 40:1289-1291 (1932).

6. Lewey FH. Neurological, medical and biochemical signsand symptoms indicating chronic industrial carbondisulphide absorption. Ann Intern Med 15:869-883 (1941).

7. Gordy ST, Trumper M. Carbon disulfide poisoning. IndMed 9:231-234 (1940).

8. Vigliani EC. Clinical observations on carbon disulfideintoxication in Italy. Ind Med Surg 19:240-242 (1950).

9. Vigliani EC. Carbon disulfide poisoning in viscose rayonfactories. Br J Ind Med 11:235-244 (1954).

10. Allen N. Solvents and other industrial organic com-pounds. In: Handbook of Clinical Neurology, Vol 36. Part1. Intoxications of the Nervous System (Vinken PJ, BruynGW, Cohen MM, Klawans HL, eds). Amsterdam:North-Holland, 1979:382-386.

11. Verberk MM. Carbon disulfide. In: Handbook of ClinicalNeurology, Vol 64. Part I. Intoxications of the NervousSystem (Vinken PU, Bruyn GW, eds). Amsterdam:North-Holland, 1994;382-389.

12. Ferraro A, Jervis G, Flicker DJ. Neuropathologicchanges in experimental carbon disulfide poisoning incats. Arch Pathol 32:723-738 (1941).

13. Lewey FH, Alpers BJ, Bellet S, Creskoff AJ, Drabkin DL,Ehrich WE, Frank JH, Jonas L, McDonald R,Montgomery E, et al. Experimental chronic carbon disul-fide poisoning in dogs: a clinical, biochemical andpathological study. J Ind Hyg Toxicol 23:415-435 (1941).

14. Richter R. Degeneration of the basal ganglia in monkeysfrom chronic carbon disulfide poisoning. J NeuropatholExp Neurol 4:324-353 (1945).

Carbon Disulfide: Frumkin'sResponseGraham offers four discrete argumentsagainst an association between carbondisulfide and olivopontocerebellar atrophy.First, he holds that olivopontocerebellaratrophy is clinically incompatible with car-bon disulfide toxicity because carbon disul-fide toxicity does not affect the cerebellumor pontine nuclei. Second, he asserts thatthe experimental studies showing extrapyra-midal involvement in carbon disulfide toxi-city relied on high-dose exposures at levelssufficient to cause apnea. Third, he is con-cerned that this experimental literature isover 50 years old. Fourth, he argues thatthe axon is more sensitive to carbon disul-fide toxicity than are other parts of the ner-vous system, suggesting that the absence ofaxonopathy rules out carbon disulfide toxi-city. Graham presents these arguments asex cathedra pronouncements and cites nobasis for any of them. In fact, each is con-tradicted by available evidence.

With regard to cerebellar involvementin carbon disulfide toxicity, Graham is fac-tually incorrect. Autopsy studies in humanswith carbon disulfide toxicity are regrettablyrare, but at least two have shown clear evi-dence of cerebellar involvement (1,2). Theanimal toxicology is far more extensive andhas been reviewed in detail (3-5); numerousreports show cerebellar involvement indiverse species including rats (6), rabbits(7), dogs (8), and cats (9). In fact, carbon

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disulfide can have quite widespread effectsin the central nervous system, leading theWorld Health Organization (10) to con-clude thatPsychic, pyramidal and extrapyramidal sympto-matology, including signs from other parts of thebrain (vestibular, cerebellar) give a picture com-patible with diffuse effects.

Graham's flat declaration that carbon disul-fide spares the cerebellum contradictsdecades of accumulated evidence.

With regard to the doses used in experi-mental studies of carbon disulfide toxicity,Graham is again factually incorrect. Hefirst expressed his curious view in a previ-ous publication (11), citing two studies forsupport. One of these studies was a primatestudy in which chronic exposure was punc-tuated by accidental high-dose exposurescausing unconsciousness (but not apnea)(12). In that study, all of the affected mon-keys recovered promptly from their acuteintoxications and resumed a steady down-hill course that continued for months. Thecerebellar damage later found in all fourmonkeys on autopsy was therefore morelikely to have resulted from chronic expo-sure than from acute anoxia. The secondstudy used dogs to test the effects of chron-ic carbon disulfide exposures (8). AlthoughLewey et al. (8) did report an increase inacute symptoms such as drowsiness andgait abnormalities immediately after thedogs were removed from test chambers,they did not mention unconsciousness,apnea, or other signs of severe acute toxicityfollowing any exposures. Severe changes inthe cortex and basal ganglia, and less severechanges in the cerebellum, were observed inthe dogs on autopsy (13). In many otheranimal studies showing cerebellar damagefrom carbon disulfide including, for exam-ple, the ones cited above (6,7,5, exposureswere chronic and at levels too low to causeacute toxicity. Thus, Graham's belief thatcerebellar damage in animals resulted fromacute toxicity with anoxia is flatly contra-dicted by the data, including the data hecited to support his belief.

With regard to the age of the experi-mental literature showing extrapyramidaleffects of carbon disulfide, Graham's rea-soning is unsound. Unlike milk, knees, andcars, scientific observations do not go badwith time. Data of any vintage are over-turned only if they are disproven by laterstudies using the same methods, or if themethods they used are later shown to beinvalid. Neither is true of the pathologicstudies discussed here.

With regard to the relative sensitivityof axons to carbon disulfide toxicity,Graham is partially correct. Peripheralnerves are certainly a primary target of car-

bon disulfide [and Graham has madeimportant contributions to our under-standing of this axonopathy (11,14)].However, both human and animal obser-vations demonstrate that central nervoussystem manifestations may occur indepen-dent of the peripheral manifestations, andmay even occur in the absence of peripher-al neuropathy. For example, in Lewey'slarge series of 120 viscose rayon workers(15), 76% of subjects had peripheral nervedysfunction and 21% had pyramidal andextrapyramidal signs; the two findingswere statistically unassociated with eachother, suggesting that they occurredthrough distinct mechanisms. In a morerecent series of 21 grain handlers with car-bon disulfide exposure, 18 had cogwheelrigidity and/or akinesia, whereas only 13had sensory loss and 7 had nerve conduc-tion velocity and electromyelographyabnormalities (16). In one of the publishedhuman autopsies, there were relativelysevere abnormalities in the cortex, cerebralvasculature, basal ganglia, cerebellum, thal-amus, pyramidal tracts, and anteriorcolumns, but only slight changes in theperipheral nerves (2). Thus, Graham iscorrect that peripheral nerve damage iscommon in carbon disulfide toxicity, buthe seems to have gone further-insistingthat axonopathy is the only lesion, and thesine qua non, of carbon disulfide toxicity.The evidence clearly shows otherwise.

Having said all this, I must admit thatit is difficult to muster too much passion indefense of a case report. A case report is,after all, only a case report. The most defin-itive evidence of exposure-disease associa-tions comes from well-designed epidemio-logic studies supported by appropriate lab-oratory data. Based on his earlier comments(17), I suspect Graham and I would agreethat such evidence would add much to ourunderstanding.

Finally, with regard to medicolegalissues, Graham is partially correct. Afterreviewing the case, forming an impression,and writing the case report, I did testify inthe trial brought by the patient and his sur-vivors (18). The jury's conclusions have lit-tle relevance to Graham's scientific concernsor my response, but because he raised theissue, I would like to provide clarification.The jury indeed found for the defendant,not because the jury members rejected alink between carbon disulfide and disease,but because they accepted the "sophisticatedemployer defense." The jury held that thedefendant, an outside firm that producedand supplied carbon disulfide to thepatient's employer, could not be held liablefor exposures that occurred on the employ-er's premises, when the employer should

have known enough to handle the carbondisulfide safely.

Howard FrumkinRollins School of Public Health

of Emory UniversityAtlanta, Georgia

E-mail: medhf@sph.emory.edu

REFERENCES AND NOTES1. Quensel F. Neue Erfahrungen Ober Geistesstbrungen

nach Schwefelkohlenstoffvergiftung. Monatschr fPsychiatr u Neurol 16:48,246 (1904). Cited in (13).

2. Abe M. Beitrag zur pathologischen Anatomie der chro-nischen Schwefelkohlenstoffvergiftung. Jap J Med SciTr Vil Int Med Pediatr Psychiatr 3:1 (1933). Cited in (13).

3. Beauchamp RO Jr, Bus JS, Popp JA, Boreiko CJ,Goldberg L. A critical review of the literature on carbondisulfide toxicity. Crit Rev Toxicol 11:169-278 (1983).

4. NIOSH. Occupational Exposure to Carbon Disulfide:Criteria for a Recommended Standard. DHEW (NIOSH)Publication No. 77-156. Cincinnati, OH:National Institutefor Occupational Safety and Health, 1977.

5. ATSDR. Toxicologic Profile on Carbon Disulfide (Update).PB/97/121073/AS. Atlanta, GA: Agency for ToxicSubstances and Disease Registry, 1997.

6. Wiley FH, Hueper WC, von Oettingen WF. The toxiceffects of low concentrations of carbon disulfide. J IndHygiene Toxicol 18:733-740 (1936).

7. Cohen AE, Scheel LD, Kopp JF, Stockell FR, Keenan RG,Mountain JT, Paulus HJ. Biochemical mechanisms inchronic carbon disulfide poisoning. Am Ind Hyg Assoc J20:303-323 (1959).

8. Lewey FH, Alpers BJ, Bellet S, Creskoff AJ, Drabkin DL,Ehrich WE, Frank JH, Jonas L, McDonald R, MontgomeryE, et al. Experimental chronic carbon disulfide poisoningin dogs: a clinical, biochemical and pathological study. JInd Hyg Toxicol 23:415-435 (1941).

9. Ferraro A, Jervis G, Flicker D. Neuropathologic changesin experimental carbon disulfide poisoning in cats. ArchPathol 32:723-738 (1941).

10. WHO. Carbon Disulfide. Environmental Health Criteria10. Geneva:World Health Organization, 1979.

11. Graham DG, Amarnath V, Valentine WM, Pyle SJ,Anthony DC. Pathogenetic studies of hexane and carbondisulfide neurotoxicity. Crit Rev Toxicol 25:91-112 (1995).

12. Richter R. Degeneration of the basal ganglia in monkeysfrom chronic carbon disulfide poisoning. J NeuropatholExp Neurol 4:324-353 (1945).

13. Alpers BJ, Lewey FH. Changes in the nervous systemfollowing carbon disulfide poisoning in animals and inman. Arch Neurol Psychiatr 44:725-739 (1940).

14. Harry GJ, Graham DG, Valentine WM, Morgan DL, SillsRC. Carbon disulfide neurotoxicity in rats: Vil. Summary.Neurotoxicology 19:159-162 (1998).

15. Lewey FH. Neurological, medical and biochemical signsand symptoms indicating chronic industrial carbon disul-phide absorption. Ann Intern Med 15:869-883 (1941).

16. Peters HA, Levine RL, Matthews CG, Chapman LJ.Extrapyramidal and other neurologic manifestationsassociated with carbon disulfide fumigant exposure.Arch Neurol 45:537-540 (1988).

17. Landrigan PJ, Graham DG, Thomas RD. Environmentalneurotoxic illness: research for prevention. EnvironHealth Perspect 102(suppl 2):117-120 (1994).

18. Charles S. Jones, individually and as representative ofthe heirs and estate of West Berry Becton, Sr. and MaryBecton v. Rhone-Poulenc, Inc., et al. Civil Action No. H-96-1904. U.S. District Court for the Southern District ofTexas, Houston Division, 28 August 1998.

Editor's note: Thepreceding letters ofGrahamand Frumkin are an inevitable but notunwelcome development for "Grand Roundsin Environmental Medicine." These lettersrejlect the nuances surrounding issues ofcausa-tion that often accompany real cases in thisarea. They also highlight the tension that candevelop among experts when these cases enterthe arena oflitigation. This is not an uncom-mon occurrence in clinical environmentalmedicine. Although providing opinions andotherwise being involved in litigation may

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provoke distaste in some medicalpractitioners,it nevertheless comprises an important duty;interestedparties and courts need expert, well-informed opinions as a basis for settling dis-putes. In the secondyear of "Grand Rounds inEnvironmental Medicine," we once againexpress our interest in receiving submissionsthat are educational, well written, and capa-ble ofwithstanding rigorouspeer review.

Howard HuMedical Editor

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NIEH Sscientists and grantees are performing basic studies of our susceptibility to environment- A part of the Nationa'lrelated disease: demonstrating that a carcinogen in cigarette smoke (benzo(a)pyrene) alters part of a Institutes of Health,gene to cause lung cancer ... showing the effects of fetal exposure to PCBs ... developing a strain ofmouse that lacks functional estrogen receptors and that helps evaluate how some pesticides and other the National Instituteestrogen-like compounds might affect development and reproduction . .. discovering the genes for of Environmental Healthbreast, ovarian, and prostate cacers... identifying women's optimal days of fertlky... seeking to reverse

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showing the effects of urban air on lung function ... North Carolina.

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