Does exposure to manganese – a toxic chemical released in welding fumes – lead to parkinsonism? That question has inspired debate in the medical and occupational health literature for years. (See “The Neurotoxicity of Manganese.”) It has also prompted more than a few lawsuits by welders, who have used data from various studies to support their claims that they have suffered from parkinsonism and other neurologic complaints as a result of manganese exposure.
Until 2003, the plaintiffs – the companies that manufacture welding rods – successfully defended against these claims. But the tide turned in a pivotal case in October 2003 – Elam v. A.O. Smith. In that case, a Madison County, IL, jury awarded a 65-year-old welder, Larry Elam, $1 million in damages, alleging that exposure to toxic welding fumes caused his Parkinson disease. He had successfully sued three companies – Lincoln Electric, Hobart Brothers, and the BOC Group – that supplied the welding rods to Union Electric in Missouri, where Mr. Elam was a welder for almost 30 years.
That decision has prompted thousands of other lawsuits by welders claiming manganese-related neurologic problems in California, Illinois, Ohio, and other states – and attention in the media. Last month, the story about the lawsuits was featured in the Wall Street Journal.
At press time, the first case comprising 6,000 claims from welders in several states – consolidated into Multi District Litigation 1535 (MDL 1535) – was scheduled to begin court proceedings in Cleveland, OH. The Ohio-based Lincoln Electric Inc., one of the largest manufacturers of welding equipment and sales — is a key defendant in the suit, as is General Electric and Caterpillar Inc., which distribute and use welding materials. Industry trade associations have also been pulled into the suits.
The counsel for the MDL plaintiffs contend that commercial manufacturers and sellers of welding rods were aware of the manganese-related health dangers for many years and failed to provide adequate safeguards in the workplace environment. (For more on the plaintiff claims, visit www.welding-rod-litigation.com.)
PIVOTAL STUDY IN LAWSUITS
As court cases alleging manganese-related parkinsonism make their way through the courts this month, Neurology Today interviewed leading PD experts, who published articles in the June 28th Neurology on the science behind the claims. They told Neurology Today that although numerous epidemiologic studies over the years have explored a possible link between manganese exposure and parkinsonism, the release of a 2001 study in Neurology (56:8–13) was a linchpin for the thousands of claims by welders.
That study – spearheaded by Brad A. Racette, MD, Associate Professor and Vice Chair of Neurology at Washington University in St. Louis – identified 15 career welders from a group of 953 parkinsonian patients who had come to the medical school's movement disorders clinic between 1996 and 2000. He and colleagues reported that the mean age of the welders with PD in that group was 17 years younger (46 years) than PD patients who were not welders.
Although the study did not provide evidence that welders were more likely to develop PD than the general population, the authors suggested that welding accelerated the onset of PD.
“Our theory is that we have identified a group of people who probably would have developed the disease eventually, but something in the welding environment caused them to develop symptoms earlier,” Dr. Racette said in a news release accompanying the release of the 2001 study.
“Our findings do not prove that manganese is the toxic agent, and other components of the fume could be responsible for parkinsonism in welders,” he and colleagues wrote in Neurology. But, they continued: “If further studies prove an increased risk of parkinsonism in welders, welding may be the first example of an environmental risk factor for idiopathic PD.”
In another study published earlier this year (Neurology 2005;64:230–235) – and now cited in the lawsuits – Dr. Racette and colleagues compared the prevalence of parkinsonism among 1,423 welders from Alabama – who had been referred by attorneys for medical-legal evaluation – against the estimated prevalence in the general population, based on published data from a 1985 epidemiologic study of Copiah County, MS.
The prevalence of parkinsonism (with a ratio of 10.2: 5.8 percent for a diagnosis of “definite PD”) among the welders was significantly higher than the estimated prevalence in the general population. Diagnoses were determined using two thresholds for diagnosis using “liberal” and “conservative” criteria. (See “Assessing Parkinsonism in Welders.”)
Investigators reported that 6 percent (by conservative standards) and 10 percent (using liberal standards) of the welders were diagnosed with definite parkinsonism and 13 percent were diagnosed with probable parkinsonism. These rates were seven to 10 times higher among active male welders, ages 40 to 69 versus the age-matched groups in the general population of Copiah County.
MRI EVIDENCE FOR TOXICITY
Keith A. Josephs, MD, and colleagues at the Mayo Clinic Department of Neurology in Rochester, MN, have also focused on a possible link between manganese exposure and parkinsonism.
He and colleagues reviewed the medical records of eight career welders – with one to 25 years on their jobs – who had been referred to his department with neurologic problems and basal ganglia TI hyperintensity on MRI (Neurology 2005;64:2033–2039).
He noted that increased T1 MRI signal in the basal ganglia is a biologic marker of manganese accumulation, and that other studies had associated welding and parkinsonism – but without MRI corroboration.
“Neurologists at the Mayo Clinic recognized that welders were coming into the clinic with neurologic abnormalities.” Dr. Josephs said, adding that no one on his research team received any external support for the study. Among the eight career welders, the study found cognitive impairment, headaches, and tremor in six patients; parkinsonism in three patients; myoclonic jerks in two patients; and balance problems in five patients.
Moreover, the welders described similar workplace conditions: inadequate ventilation, confined spaces, and a lack of respiratory protection.
“Welding is a common occupation, and the association of welding with a medical condition does not necessarily imply that toxins from welding are the cause,” Dr. Josephs and colleagues wrote.
The authors continued: “However, circumstantial evidence suggests that welding-related manganese neurotoxicity may have been causative in these cases for several reasons: 1) the MRI T1 basal ganglia hyperintensity, which is a relatively specific biomarker of brain manganese accumulation; 2) the overlap of symptoms and signs among these patients; 3) shared clinical features with previously described cases of manganese neurotoxicity, for example, tremor and parkinsonism; 4) inadequate ventilation or protection during welding, which may predispose to manganese toxicity.”
“On the other hand, some of the symptoms experienced by these patients are less specific, such as headache or irritability, and could have been coincidental in some cases. The precise clinical spectrum of welding-related manganese neurotoxicity requires further study and confirmation,” the authors concluded.
HOW TO MAKE SENSE OF THE DATA
These data notwithstanding, several PD experts expressed skepticism about a direct causal link between manganese in welding fumes and parkinsonism.
In a literature review, Joseph A. Jankovic, MD, Professor of Neurology and Director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston, agreed that manganese can cause an intoxication resulting in a neurologic syndrome associated with dystonia, dysphonia, cognitive impairment, emotional disturbances, and some features of parkinsonism (Neurology 2005;64:230–235). But, he said, there was no convincing evidence for an association between welding and PD.
He told Neurology Today: “There is no convincing epidemiologic data to show welding causes either parkinsonism or Parkinson disease. In some instances, it is not just the manganese in fumes [that people have made an issue of], but it could be the ventilation. It's a giant leap to link the manganese with parkinsonism.”
Several epidemiologic studies have attempted to address the question whether welding is a risk factor for PD or other neurologic disorders, he noted. A 1947 survey by the US Public Health Service of 4,650 shipyard workers, three-quarters of whom were welders, found no evidence that these workers had an unusually high occurrence of parkinsonism or any other neurologic disorder.
In a study involving the World War II Veteran Twins Cohort, in which 142 twin pairs were identified where one twin had PD, welding was not associated with PD (Neurology 2003;60(suppl 1):A415). Several mortality surveys of large populations of welders found elevated rates of digestive tract cancer, accidental trauma, stroke, lung cancer, cirrhosis, suicide, and heart disease, but not of PD or any other neurologic disease (Medical Research Council 1995;23–61).
“One of the most cited studies is that of Bowler et al., who evaluated 76 welders, with an occupational history of 25 years, and compared them to 42 controls [Int J Hyg Environ Health 2003;206:517–529],” he wrote.
“The two groups performed similarly on tests of verbal skills, verbal retention, and auditory spans, but welders performed worse than controls on tests of verbal learning, working memory, cognitive flexibility, visuomotor processing speed, and motor efficiency.”
Furthermore, welders had more complaints related to emotional and physical well being. This study, however, has been criticized because of many methodological problems, including the fact that welders had a lower educational background than controls.
“Also, no attempt was made to correlate the abnormal neuropsychological findings with dose or duration of exposure. Furthermore, there was an obvious selection bias as the welders were recruited into the study because they filed civil and Workman's Compensation litigation claiming that their symptoms were related to occupational welding.”
“For these and other reasons,” Dr. Jankovic wrote, “there is no justification for the conclusion that neuropsychological testing is an effective means for assessing manganese toxicity.”
MANGANESE TOXICITY CLUSTERS
Dr. Jankovic also reviewed results from an outbreak of manganese toxicity in a cluster of Taiwanese miners. In that study, he explained that investigators reported that the typical symptoms of manganese-induced parkinsonism were attributable to a “malfunctioning ventilating system, raising ambient levels of manganese to toxic levels in excess of 27 mg/m3 [Arch Neurol 1989;46:1104–1106].”
“Fumes generated during the welding process are formed by the vaporization of metals under conditions of extreme heat (2,000 to 3,000 centigrade temperatures) and the subsequent condensation with iron results in a tightly bound, non-soluble, iron-manganese amalgam, making transportation of any free manganese across blood–brain barrier unlikely [Toxicol Appl Pharmacol 2001;1700:79–87],” Dr. Jankovic wrote.
These and other studies demonstrate the dearth of evidence that welding fumes contain sufficient amounts of free and soluble manganese to actually enter the blood and brain, strongly arguing against any neurotoxic effects of manganese from welding, he said.
Regarding the 2001 study by Dr. Racette, which spurred legal action by welders, Dr. Jankovic noted that there were methodological weaknesses.
“There is a real selection bias here. The patients were not randomly selected and therefore we cannot conclude that the study population is representative,” Dr. Jankovic said.
In addition, Dr. Jankovic said that the 2001 study suffers from referral bias, because the entire group was referred to a tertiary care center, where the sickest patients are referred.
And because there was a family history of PD in eight of 15 welders, a rate much greater than 15 percent in unselected PD patients, Dr. Jankovic questioned whether genetics was a major risk factor in that population. Moreover, Dr. Jankovic contended: “If welding was an important risk factor for Parkinson disease, it would become apparent in large clinics like ours.”
Asked to comment on Dr. Jankovic's opinions, Dr. Racette responded by e-mail: “We stated in our manuscript the strengths and weaknesses of our study. Strengths include screening of all subjects by movement disorders experts and a large sample size. Weaknesses of our study include possible reviewer bias since our video reviewers know that many of the subjects were welders. However, the reviewers did not have any specific information on the degree of welding exposure.”
FEW WELL-DESIGNED CASE-CONTROL STUDIES
Karl Kieburtz, MD, and Roger Kurlan, MD, both from the University of Rochester, also wrote an editorial on the state of the science for welding and Parkinson disease in the June 28th Neurology (64:2001–2003).
In a phone interview, Dr. Kieburtz told Neurology Today: “The absence of finding a relationship does not prove the absence of relationship. Many of the past studies did not use careful definitions of welding exposure or of case definitions of parkinsonism or PD. That said, the case-control studies in population-based samples published to date have indeed failed to find any meaningful association between PD and manganese exposure. To date, there have been no well-designed case-control studies assessing the relationship between welding exposure per se and PD.”
Dr. Kieburtz agreed that manganese in excess can cause neurologic abnormalities, but he said welding fumes include a complex mix of other heavy metals and substances, which could also be neurotoxic.
For example, he said, iron, a major component of fumes, increases oxidative stress through the formation of free radicals and provokes neuroinflammation.
Dr. Kieburtz and colleagues also questioned the methodology in both of Dr. Racette's papers. They faulted the 2001 study for using a control group that was not age-matched, which they contended “may have represented an age effect of sampling individuals still employed to those who were largely retired.” And they raised concerns about the control group in the 2005 study because Dr. Racette used historical controls. They wrote: “The observed prevalence of parkinsonism in the welders was high, but it is not clear that the rate was higher than an appropriate control group.”
As for the MRI study by Dr. Josephs and colleagues, Dr. Kieburtz said it was premature to tell what it means. “It is not clear whether it is a specific syndrome or a coincidental finding,” he said. The authors make the tentative assumption that the welders with MR abnormalities have manganese intoxication. This assumption warrants further investigation and substantiation, he said.
“The difficulty in interpreting the results of such a small case series is that the coexistence of welding with these phenomena does not demonstrate a causal relationship.”
As for determining causation, he said: “It's a very tricky business. Latency can take years to decades. What we need are very well-designed studies to answer the question.” That said, he pointed out that the issue might not get settled because there is so much of a litigious climate.
DISCLOSURE OF CONFLICT OF INTEREST
Many experts who are researching and writing on this topic have been involved in one side or the other of the litigation, providing expert testimony, research data, or both. In fact, Dr. Kieburtz noted that in his editorial, writing: “…the reader (and the writer) need to be careful about recognition and disclosure of potential conflicts of interest.”
Dr. Kieburtz acknowledged that he has received research support from General Electric. GE and its subsidiaries are frequently the lead defendant in many of the suits.
Dr. Jankovic disclosed in his review article that he has received support from General Electric and the National Parkinson Foundation. Dr. Josephs, lead author of the MRI study said that his research was conducted without outside funding. However, attorneys have been trying to use it to mount their case.
Questions about the objectivity of authors in the peer-review literature also apply to those working with plaintiffs. When Neurology Today asked Dr. Racette to comment on the influence of plaintiffs on his research, on advice of his attorneys, he responded by e-mail: “There was no plaintiff or defense attorney support for our initial study in 2001. In our 2005 study, we acknowledge financial support from plaintiffs' attorneys for medical screening. However no author in our study has received any money personally related to this study. We believe that reduces bias.”
Some neurologists questioned whether the litigation would hinder resolving the issues scientifically. “As soon as you get the legal profession involved, it is very hard to get a good study,” Kathleen Shannon, MD, Associate Professor of Neurology at Rush University in Chicago, told Neurology Today. The defendants and plaintiffs are funding most of the current research, she explained. Precisely for that reason, her institution chose not to participate in a large multicenter trial seeking to examine the issue – again – on welding fumes and parkinsonism, citing the potential for conflicts of interest.
CRITERIA FOR PARKINSONISM IN WELDERS
Dr. Brad A. Racette used the following criteria in his 2005 study to assess parkinsonism in welders:
* For “definite parkinsonism,” the patients had to have any three of the following clinical signs: rest tremor, rigidity, bradykinesia, postural instability; or two of the following: asymmetric rest tremor, asymmetric rigidity, asymmetric bradykinesia, and postural instability.
* For probable parkinsonism, any two of the following: rest tremor, rigidity, bradykinesia, or postural instability; or 1 of the following asymmetric features: rest tremor, bradykinesia, or rigidity.
* The conservative standards for the criteria required bradykinesia greater than 1.5 in at least 2 limb ratings on the UPDSR3, and postural instability greater than 2 on UPSRD3.
* The liberal standards for the criteria required bradykinesia greater or equal to t+1 in at least 1 limb rating on the UPDSR3, and postural instability greater or equal to 1 on UPDSR3.
THE NEUROTOXICITY OF MANGANESE
George Cotzias, MD, a neurologist and biochemist, began studying the role of manganese in parkinsonism in the 1950s. Dr. Cotzias was interested in the biochemical aspects of metabolism and nutrition, focusing on the effect of trace metals, such as manganese, in cell function.
In a series of basic studies over the following decade, he elucidated the distribution, absorption, elimination kinetics, and probable function of manganese.
He also became interested in its neurotoxicity, based on reports of neurological symptoms of Chilean miners excavating manganese ore. He reported that their symptoms were similar to those of Parkinson disease.
Manganese poisoning ultimately proved an experimental model for Parkinson disease. Dr. Cotzias and colleagues subsequently demonstrated the therapeutic effect of L-dopa, a precursor of dopamine, initially on chronic manganese poisoning and later on in patients with Parkinson disease.
ARTICLE IN BRIEF
✓ The article discusses new lawsuits alleging that manganese exposure causes parkinsonism and the most recent articles in Neurology, which provides a review of the scientific evidence for these claims.