A Reply to “Neuropsychologic Impairment, MRI Abnormalities, and Solvent Abuse”

To the Editor:

I appreciate the comments made by Dr. Meggs and realize the difficulties that toxicologists with limited neurological expertise have in assessing the very confusing solvent neurotoxicity literature that has been published over the past three decades [1]. But it is nowhere near as confusing as to how the entire focus of his comments is related to 14 words out of a total of almost 8000 from our paper [2]. His comments are not about the study we published, but about a syndrome with serious questions about both its validity and existence: the occupational exposure to organic solvents and the resulting non-specific subjective symptoms, the so-called “psycho-organic syndrome,” previously called the “painters syndrome” since it was first described in Denmark in industrial painters. Dr. Meggs prefers the terms “solvent neurotoxicity or organic solvent syndrome” which are both misleading and inaccurate.

Dr. Meggs and all the readers of our study need to understand several critical issues regarding its relationship to the occupational solvent neurotoxicity literature:

1. Our study was in inhalant abusers. These individuals voluntarily dose themselves with levels of solvents that are at minimum a magnitude higher than that which occurs in the occupational setting.

2. Our study subjects dose themselves on a regular basis (daily to several days per week) with levels that are enough to induce an acute encephalopathy often to the point of general anesthesia.

3. Solvent inhalant abusers are a group of individuals who have proven neurotoxicity in the way of definite pathological changes of the central nervous system. In the situation of ”solvent neurotoxicity or organic solvent syndrome” related to occupational exposure referred to by Dr. Meggs no pathologic alteration of the brain has been demonstrated.

4. As opposed to inhalant abusers—where significant permanent neurological injury may occur from solvent inhalation—there is a lack of clinical reports that describe permanent neurological deficits due to occupational solvent exposure.

5. As opposed to chronic inhalant abuse, there is a lack of epidemiological studies that describe either a coherent clinical syndrome or pathological changes in occupational solvent exposure.

6. Dr. Meggs notes that “difficulty with memory and cognition are often the initial subjective complaints associated with neurotoxins, including solvents.” We have been struck by the often complete lack of subjective symptoms in inhalant abusers, despite their obvious neurological impairment. This is in keeping with other dementing disorders, such as Alzheimer's disease, where typically the family, rather than the patient, complains and brings the patient to the physician for evaluation.

7. The occupational syndrome is almost exclusively limited to compensatory situations such as worker's compensation cases or tort litigation. It is rare to evaluate such a patient who does not already have legal representation or has not had an attorney arrange for medical assessment. Issues of both primary and secondary gain severely limit the conclusions that one can draw from study of this group of individuals. This does not occur with the inhalant abuser, who avoids the medical community unless seriously ill, requiring emergency treatment, and typically only has legal representation when their abuse—or complications of their abuse—has caused them to come into contact with law enforcement officers.

With this being said, now Dr. Meggs suggests that the lack of finding in both our study and in a few studies of occupational exposure to solvents of a dose-response relationship (with neuropsychological testing only) means that a dose-response relationship does not exist. The focus of his criticism is that we did not find a dose-response relationship with neuropsychological testing. However, we did find a dose-response relationship with MRI.

It is this discrepancy which is important. While neuropsychological testing is important in the assessment of cognitive impairment from all causes, it is the reliance on these highly sensitive (for detecting cognitive impairment) but highly non-specific (for determining etiology of cognitive impairment) for defining what should be a neuropathological condition. The work that we have done in inhalant abusers over the past 20 years has been to define the neuropathology of solvent neurotoxicity—in a high dose situation-in order to better define the much lower dose, yet more prevalent situation that occurs in the workplace. We have chosen this group of individuals to study, not only because they develop clear-cut and specific neuropathology (unlike those exposed to solvents in the occupational setting) but also because there does not exist an animal model which demonstrates neuropathological changes. So our theory from the inception of our work has been that understanding a high-dose situation in humans is essential to understand lower levels of exposure.

It has been clear from our earliest studies [3][4][5][6][7][8] that only those individuals (approximately 10% of the total number of chronic inhalant abusers) with the most extreme abuse develop evidence of neurotoxic injury of the brain. These are the individuals who develop neurological abnormalities, including cognitive impairment characterized by subcortical involvement. For a better understanding of the pathology, we coined the term “white matter dementia” because this is one of the pathological hallmarks of solvent-induced neurotoxic injury [8]. These abnormalities never occur from occupational solvent exposure, which is diagnosed by subjective complaints which are then “verified” by having virtually any type of abnormality on neuropsychological testing (since no consistent abnormality has been defined on these tests). Furthermore, the neuropsychological test abnormalities are never verified by other more objective tests, and are never correlated to any kind of pathological alteration of the nervous system.

While it is possible that different types (based upon intensity and duration) of exposure can result in different clinical pictures, what is the site of pathology—the hallmark of neurotoxic injuries—in the occupational exposure setting that results in neuropsychological test abnormalities that Dr. Meggs feels is sufficient to define a lack of a dose-response relationship? I would offer the suggestion that based upon the studies in inhalant abusers that the occupational syndrome is completely fictitious. The strongest indictment of this belief is the paper published by the Danish group who first defined the solvent syndrome, which essentially was published as a retraction of their seminal work a decade earlier [9].

This group's initial studies, based on non-standardized tests, did not contain control groups [10][11]. Testing consisted of neuropsychological tests, and on retesting two years after the initial study, performance was unchanged. The 1988 study compared the scores of the original group of 20 solvent-exposed individuals with the scores of 20 non-exposed control subjects. The control group was a subsample of 120 non-exposed controls that were individually matched to each of the 20 solvent-exposed patients on age, sex, and education. When compared with these controls, the previously reported solvent-exposed individuals had no evidence of intellectual impairment.

These results are similar to those of other studies in which control groups were matched on premorbid levels of intelligence, or when statistical corrections are made for differences in intelligence. These negative results are also consistent with results from cross-sectional psychometric studies of solvent-exposed workers and control subjects, where group differences have generally been small, acute effects of solvent exposure have not been anticipated, and dose-response relations were not seen. A critical analysis of the hundreds of studies that have been performed over the last two decades addressing this issue of solvent neurotoxicity-and not just the four cited by Dr. Meggs—will verify this observation.

Since we have demonstrated a dose-response relationship with MRI, why the concern by Dr. Meggs over the type of testing demonstrating the response? Even if we were to ignore the volumes of research to the contrary and that the dose-response relationship is the basic tenet of toxicology, how are we to address Dr. Meggs' comment that essentially states that the absence of evidence of a dose-response relationship (at least with neuropsychological testing) is evidence of absence of a dose-response relationship?

We are all familiar with the words of Paracelsus (1493–1541): “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” This statement has become the basis of the definition of what a poison is and the dose-response relationship in the field of toxicology [12]. While there are clearly situations where factors other than dose are important (such as individual variability of response as suggested by Dr. Meggs), dose is still the most important factor when it comes to neurotoxic injuries [13] and also when it comes to neurotoxic injuries related to solvents, as we have demonstrated in the study in question here. I am not aware of any study that would suggest that there is any significant variability of response to solvents in humans as regarding the development of any type of neurological injury, be it central or peripheral nervous system. The studies cited by Dr. Meggs—neuropsychological studies in occupational exposure to solvents—show lack of a dose-response relationship. I contend that those studies suggest a lack of evidence of a neurotoxic injury rather than a lack of a dose-response relationship.

Our study of a true neuropathological condition—solvent-induced brain injury (emphasis on the word “injury”)—demonstrates that neuropsychological studies, while sensitive for picking up cognitive abnormalities do not demonstrate a dose-response relationship. This does not mean that there are not abnormalities on the testing in these individuals. If one were to read the study, it is clear that not only the solvent inhalant abusers, but also the comparison group (mostly cocaine abusers) have significant abnormalities on neuropsychological testing. Without a dose-response relationship, the suggestion is that many other factors may be affecting the performance of these individuals, including other drug effects and emotional factors. Neuropsychological tests cannot separate those effects from the actual effects of the solvents.

In my experience, the “organic solvent syndrome” that Dr. Meggs refers to exists in this country primarily within the confines of the legal system, thereby adding additional confounding factors which can affect neuropsychological test results. The stress and the primary and secondary gains afforded to the process of litigation have been demonstrated in innumerable studies to affect results of neuropsychological tests and certainly cannot be used to define a pathological process affecting the brain. The purpose of our work over the past 20 years with inhalant abusers is to study a high-dose situation and try to devise sensitive and specific means of diagnosing solvent-induced brain injury. So far, MRI has proven to be superior to all other modalities, though continued work is required to find the optimal imaging sequences.

While I will continue to utilize neuropsychological tests in the assessment of individuals with cognitive complaints that require more detailed assessment than I am capable of as a neurologist, I will not allow those results to define a neurotoxic syndrome than has neither neuropathological alteration nor neuroanatomical abnormality. This is especially true with solvent-induced neurotoxic injury since MRI has proven to be both sensitive and specific in this regard.

Neil L. Rosenberg, M.D.

Division of Clinical Pharmacology and Toxicology

University of Coloroado School of Medicine Denver, Colorado, USA