Personalized Prevention in Mercury-Induced Amyotrophic Lateral Sclerosis: A Case Report

Round 1

Reviewer 1 Report

Thank you for asking me to review this single case study of Chronic exposure to low level of mercury in the development of motor neuron diseases (MND). It is very well written and provides solid arguments that show biological plausibility. The systematic review by Fields et al. on “Mercury-induced motor and sensory neurotoxicity: systematic review of workers currently exposed to mercury vapor” provides significant evidence of the neurotoxic effects following environmental/occupational exposure to mercury vapor. Furthermore, the evidence provided by Llop et al. on several epigenetic and genetic characteristics have been associated to Hg neurotoxicity. The novelty here is the link between the two pieces of evidence to detect any genetic predisposition to ALS following Chronic Hg poisoning. The concern in this case study is, as the authors themselves acknowledged, that it is a single case study and therefore such a plausible link needs to be followed up by more case studies. I suggest that this needs to be emphasized with more strength than it is - a limitation that is not covered simply by the fact that this case study has a twenty year occupational history.  This is more so when the case highlights the important role of genetics in personalized occupational medicine and that the recommendation is that occupational physicians should use genetic tests to identify conditions of individual susceptibility. Nevertheless, the authors do qualify that this should be done in workers with documented frequent episodes of mercury intoxication recorded during health surveillance programs to customize prevention measures in the workplace, and act before damage appears. 

Author Response

Response: We thank the reviewer for appreciating our work. We had a hard time explaining very complex reasoning in a few words. In the revised version of the manuscript we have replaced the lines 199-202 with the following text:

“The intervention of the occupational physician to prevent occupational mercury intoxication should be directed primarily at modifying the environment, rather than at assessing the worker's adaptation to the job. However, a small maintenance contractor has little chance of influencing the chlor-alkali plant safety strategy. In these cases, the decision to allow exposure to risk, declaring the worker "fitting for the job", or to declare him unfit, exposing him to dismissal, is very difficult. Even if the causes of ALS are multifactorial and a single gene mutation might not be sufficient to cause ALS, personalized occupational health practices, searching for genetic biomarkers of susceptibility in selected cases with documented frequent episodes of mercury intoxication recorded during health surveillance programs, could be an aid in the doctor's decision, allowing to customize prevention measures in the workplace and acting before serious and irreversible consequences of occupational exposure appear”.

Reviewer 2 Report

1. Elemental mercury is a silver-grey liquid at room temperature, which vaporizes slowly. Mercury is produced mainly from the cinnabar ore. Secondary mercury is recovered from heating scrapped mercury-containing products and industrial waste. Organic compounds (such as methyl mercury) are generally not considered today as major occupational risks. This case was exposed to methylmercury and then developed amyotrophic lateral sclerosis, so it is worthy of attention.
2. Because the primary source of exposure to methyl mercury is non-occupational, such as seafood consumption. The author should provide the habit of seafood consumption of this patient.
3. Is there workplace air monitoring data of mercury in the Chlor-alkali plant?
4. Delete line 68-79.
5. Provide the golden diagnostic criteria for ALS.
6. Is there renal function impairment? It’s essential to screen for the adverse effect of mercury intoxication.
7. Because the causes of ALS are multifactorial and a single gene mutation might not be sufficient to cause ALS. The use of gene screening in workers to prevent occupational diseases is controversial and has no clinical evidence. I suggest the author delete or modify the opinion “genetic testing for selected workers would be a valuable and cost-effective primary prevention measure. Personalized occupational health practices, searching for genetic biomarkers of susceptibility in selected cases, allow to avoid serious and irreversible consequences of occupational exposure.” (line 199-202). In the principal of occupational health, we must fix the workplace, not the workers.

Author Response

Reviewer #2

1. Elemental mercury is a silver-grey liquid at room temperature, which vaporizes slowly. Mercury is produced mainly from the cinnabar ore. Secondary mercury is recovered from heating scrapped mercury-containing products and industrial waste. Organic compounds (such as methyl mercury) are generally not considered today as major occupational risks. This case was exposed to methylmercury and then developed amyotrophic lateral sclerosis, so it is worthy of attention.

Response: We absolutely agree. Mercury used in chlor-alkali industrial plants is an air pollutant. Mercury cell chlor-alkali plants produce chlorine and caustic using mercury cells. In the USA, the Clean Air Act required EPA to identify categories of industry or “source categories” that emit seven specific air pollutants (including mercury). Chlor-alkali plants are among the source categories emitting the 90 per cent of mercury. On August 25, 2003, the Environmental Protection Agency (EPA) issued a final rule to reduce emissions of mercury from mercury cell chlor-alkali plants. The final rule required rigorous work practice standards such as periodically washing down work floors and covering waste containers, new control devices, monitoring, recordkeeping and reporting. Similar rules were issued in Italy, too. These requirements reduced mercury air industrywide emissions from so-called “fugitive sources” throughout the plants. We thank the reviewer for appreciating our work.

2. Because the primary source of exposure to methyl mercury is non-occupational, such as seafood consumption. The author should provide the habit of seafood consumption of this patient.

Response: The reviewer did well to remind us of this point. We have added this information. The patient followed the Mediterranean diet, consuming fish on average 3-5 times per month.

3. Is there workplace air monitoring data of mercury in the Chlor-alkali plant?

Response: Certainly, in the plant, there was a monitoring of the environmental levels of mercury; unfortunately, the patient was not in possession of the environmental measurements, which are never communicated to individual workers.

4. Delete line 68-79.

Response: Sorry about the typo. Many thanks for reporting this error.

5. Provide the golden diagnostic criteria for ALS.

Response. We have indicated the most commonly used criteria for diagnosis.

6. Is there renal function impairment? It’s essential to screen for the adverse effect of mercury intoxication.

Response: Kidney function was normal.

7. Because the causes of ALS are multifactorial and a single gene mutation might not be sufficient to cause ALS. The use of gene screening in workers to prevent occupational diseases is controversial and has no clinical evidence. I suggest the author delete or modify the opinion “genetic testing for selected workers would be a valuable and cost-effective primary prevention measure. Personalized occupational health practices, searching for genetic biomarkers of susceptibility in selected cases, allow to avoid serious and irreversible consequences of occupational exposure.” (line 199-202). In the principal of occupational health, we must fix the workplace, not the workers.

Response: We absolutely agree with what the reviewer said. The point indicated is in fact very critical, and it is not easy to summarize our thinking correctly in a few lines. We have tried to summarize as follows:

“The intervention of the occupational physician to prevent occupational mercury intoxication should be directed primarily at modifying the environment, rather than at assessing the worker's adaptation to the job. However, a small maintenance contractor has little chance of influencing the chlor-alkali plant safety strategy. In these cases, the decision to allow exposure to risk, declaring the worker "fitting for the job", or to declare him unfit, exposing him to dismissal, is very difficult. Even if the causes of ALS are multifactorial and a single gene mutation might not be sufficient to cause ALS, personalized occupational health practices, searching for genetic biomarkers of susceptibility in selected cases with documented frequent episodes of mercury intoxication recorded during health surveillance programs, could be an aid in the doctor's decision, allowing to customize prevention measures in the workplace and acting before serious and irreversible consequences of occupational exposure appear”.