LETTERS TO THE EDITOR

authors’ recognition of this event dramatically highlights the importance of a physician assessing clues from many sour- ces-including such “unscientific” ones as the patient’s spouse. Nonetheless, this presentation raises the following inquiries: Is the case adequate to draw a valid inference about human toxicity of carbaryl? Second, should the Jour- nal combine an abbreviated case study with a literature review?

In regard to the first question, the diagnosis hinges on “low” serum pseudocholinesterase levels that rise after termination of exposure. No pre-exposure levels are avail- able to verify the meaning of this finding. Also, the possibili- ties of aging or accumulated exposure to other toxins are addressed by stating ‘I. . . extensive series of investigations failed to determine the cause . . .I’ and by adding that ‘I. . . the opinions of an internist, cardiologist, neurologist and an orthopedist . . .I’ were obtained at some point by the pa- tient. In short, the reader cannot form his or her own differential diagnosis for this case. Therefore, we propose that the case presentation is not adequate to demonstrate an effect of carbaryl exposure. In contrast, the authors state I‘ . . . an observation . . . established the diagnosis.” We disagree; we believe it can do no more than suggest a diagnosis.

Finally, let us turn to the second question. Have the editors accepted a causal association between carbaryl exposure and human neurotoxicity? Their abbreviated title found in the upper corners of each page of the article is “Chronic Neurotoxicity of Carbaryl.” Note that there is no question mark. To this assertion, the editors might reply that the title is ambiguous with regard to human or animal toxicity. In turn, we would point to the context, i.e., the article is in a medical journal, not a toxicologic one.

Physicians need to be aware of the effects of pesticides on human health [ 11. Perhaps long-term effects of some pesticide exposures will be revealed in the future. However, the demonstration of long-term cause-and-effect relation- ships is a rigorous task. This task requires the use of case- control studies followed by prospective studies [2,3].

In the future, will abbreviated case reports be sufficient to establish new toxicologic syndromes? We hope not.

MICHAEL K. McEvov, M.D. STANLEY H. SCHUMAN, M.D., Dr.P.H.

Agromedicine Program Medical University of South Carolina

Department of Family Medicine Charleston, South Carolina 294252217

I. Hallenbeck WH, Cunningham-Burns KM: Pesticides and human health, 1985.

2. Linz DH, Degarmo PL, Morton WE, et al: Organic solvent-induced encephalopathy in industrial painters. J Occup Med 1986; 28: 119-125.

3. Sandifer SH, Cupp CM, Wilkins RT, Loadholt B, Schuman SH: A case-control study of persons with elevated blood levels of dieldrin. Arch Environ Contam Toxicol 1981; 10: 35-45.

Submitted June 6, 1986, and accepted August 29, 1986.

The Reply: We welcome the opportunity to respond to the critique of our review article “Is Carbaryl as Safe as Its Reputation?”

and the accompanying case report “Subacute Neurotoxic- ity following Long-Term Exposure to Carbaryl” in the April 1986 issue, as it provides an opportunity to clarify the objectives of our somewhat unusual approach in presenta- tion.

The initial and major critique is Drs. McEvoy and Schu- man questioning the validity of drawing the inference that long-term exposure to carbaryl can cause neurotoxicity in humans. The criteria for establishing a cause/effect associ- ation between a potential toxin and an adverse response include the following: (1) The toxin should have the potential to induce the adverse response; (2) There should be a temporal relationship between onset and offset of toxicity and the time of exposure to the toxin; (3) There should be objective biochemical evidence of the presence of toxin: and (4) Re-exposure should be associated with a recur- rence of the toxicity. When these criteria are applied to the index patient, carbaryl can cause chronic irreversible neu- rotoxicity in pigs and, therefore, could feasibly do so in humans. There was a close temporal relationship between toxicity observed in this patient and both initial exposure and withdrawal of exposure. There was also objective evi- dence of the presence of an anticholinesterase drug, since plasma and red cell pseudocholinesterase levels were low at the time of peak toxicity and subsequently returned to normal. There was no evidence of liver disease or other abnormality to account for the low levels of enzyme activi- ty, and the lack of a pre-exposure measurement can hardly be construed as a realistic objection to the diagnosis. The only criterion that was not formally challenged was re- exposure. However, it was notable that the initial “clean- ing” of the patient’s house was not associated with either an improvement of symptoms or a return to normal of plasma pseudocholinesterase levels. It was only after relo- cating his home and dispossession of his belongings that there was an improvement in both, suggesting that contin- ued exposure was associated with continued toxicology. It was not considered ethically justifiable to re-expose the patient to long-term carbaryl at a later time. Overall, there- fore, we considered that there was a reasonable basis for reaching a diagnosis.

We would agree that, for the sake of brevity, the case report did oversimplify a complex situation. However, it should be noted that once the diagnosis was considered, the internist, cardiologist, neurologist, and orthopedist all agreed that long-term carbaryl exposure was the most likely cause of the patient’s clinical syndrome.

If the index patient’s syndrome was attributable to carba- ryl, were we justified in presenting a single case history? We believe so. Given that: (1) Carbaryl is extensively used in homes; (2) It undergoes minimal degradation in a dry, dark environment and, therefore, has the potential to accu- mulate with repeated application (carbaryl was still detect- able in dust, removed from the index patient’s house at the time of diagnosis, seven years later): (3) Carbaryl can be absorbed via pulmonary, cutaneous, and oral routes; and (4) there was the insidious presentation of a severe toxicologic syndrome in the index patient following long-term exposure to carbaryl, we considered that the medical community should be made aware of the possible association in the hope that, by raising the index of suspicion if a similar

December 1986 The American Journal of Medicine Volume 81 1125

LETTERS TO THE EDITOR

diagnosis is made in other patients, removal of exposure could have a dramatic beneficial effect for those patients.

Drs. McEvoy and Schuman also criticize the editors of the Journal for combining a case study with a literature review. The presentation of a full review rather than a short discussion in the case report was prompted by the lack of critical information, rather than the presence of informa- tion, required to address the potential risk of carbaryl in causing chronic toxicity in humans. In this review, we tried to present not only the limited information available, but also indicate what additional information should be avail- able. We would agree with Drs. McEvoy and Schuman’s comment “the demonstration of long-term cause-and-ef- fect relationships is a rigorous task,” but believe that their subsequent comment “this task requires the use of case- control studies followed by prospective studies” is far too limited. When faced with a patient with a chronic neurologic illness after excessive exposure to carbaryl, we asked the question, is carbaryl known to cause chronic neurotoxicity? Experiments in most species of animals did not have ade- quate dosage ranges to address this question, and in the one instance in which there was positive evidence, there were no pharmacokinetic data of carbaryl’s disposition in pigs or humans to permit rationale extrapolation between animal and human toxicology. Similarly, evidence in hu- mans was meager. No published evidence was available on the effect of long-term exposure at levels associated with toxicity.

A familiar concept in therapeutics is that there is wide intersubject variation in response to any drug, such that a minority of subjects exposed to a given dose of a drug may have an adverse response. Such a phenomenon would also be anticipated for an environmental hazard like carbaryl. The mechanisms responsible for these idiosyncratic re- sponses are varied, but include factors that contribute to intersubject variations in drug disposition and drug re- sponse. One possible explanation for adverse reactions occurring in a minority is if drug metabolism is less efficient that normal, continued exposure will result in greater drug accumulation, which could result in a response only nor- mally seen with higher levels of exposure. These factors may well be relevant in the index patient who was elderly, often associated with slower rates of drug metabolism, and receiving cimetidine, a known inhibitor of oxidative drug metabolism.

There is, to our knowledge, no system equivalent to the Food and Drug Administration for reporting adverse drug reactions for collating experience observed by individual physicians for environmental hazards. In the absence of any formal reporting system for adverse reactions possibly associated with insecticide exposure, we believed it impor- tant to present this information to the medical community and raise the question “Is carbaryl as safe as its reputa- tion?,” hopefully stimulate others to address the important questions raised, and indicate that these questions do not have adequate answers at the present.

STEPHEN WARD, Ph.D. A. BRANCH, M.D., F.R.C.P.

Department of Pharmacology Vanderbilt University School of Medicine

Nashville, Tennessee 37232

PUBLICATION INVESTtGATlON

To the Editor: A little over a year ago, a charge of research fraud was made against Dr. Robert A. Slutsky, a former member of the Departments of Medicine and Radiology at the University of California, San Diego. Following the procedures of the School of Medicine, an ad hoc committee was appointed to investigate the merits of the charge. Examining recently submitted and published papers and other records, the committee concluded that fabricated research findings had been submitted and published. A formal investigation committee was then given the responsibility to review all of Dr. Slutsky’s publications and attempt to decide if any others were invalid, and to determine the role of the co- authors.

This committee believes that the burden of proof of validity rests on the authors of the publication. In view of the unreliability of Dr. Slutsky’s work, the investigating commit- tee has taken the position that any of his papers must be considered questionable if no co-author could vouch for the validity of the collected data and their analysis, and the accuracy of the final publication in recording actual meth- ods and results.

After consulting extensively with Dr. Slutsky’s co-au- thors, the committee classified each paper as (1) valid, (2) questionable, or (3) fraudulent. The committee was satis- fied that none of the co-authors has participated in or had knowledge of fraudulent practices. In most cases, Dr. Slutsky’s unwillingness to share raw data or allow others to perform analyses or to participate in manuscript prepara- tion and revision inhibited detection of invalid statements before publication; in other cases, names were used on manuscripts without knowledge or permission, or the named co-authors were trainees and unable to review Dr. Slutsky’s work.

The investigating committee has found no reason to doubt the validity of the following publication, and requests publication of the following statement:

An investigation by an ad hoc faculty committee of the University of California, San Diego School of Medicine into the work of Dr. Robert Slutsky has found evidence of research fraud in certain of his publications. The committee has placed the burden of proof on co-authors to establish the veracity of the experiments and methods reported in his other publications. The committee’s examination of the paper listed below and the testimony of co-authors did not result in concern about the validity of the publication:

ID number: 11 Slutsky RA, Ackerman W, Karliner JS, Ashburn WL,

Moser KM: Right and left ventricular dysfunction in patients with chronic obstructive lung disease. Am J Med 1980; 68: 197-205.

RICHARD M. PETERS, M.D. Chair, Ad Hoc Committee

PAUL J. FRIEDMAN, M.D. Associate Dean, Academic Affairs University of California, San Diego

School of Medicine La Jolla, California 92093

1126 December 1966 The American Journal of Medicine Volume 61