VACCINES AND AUTISM
Institute of Medicine hears clashing evidence on whether vaccine preservative causes autism
BETTE HILEMAN, C&EN WASHINGTON
since the mid-1990s, debate has raged over whether vaccines routinely given to infants and toddlers may contribute to the development of autism. In particular, some people believe the preservative thimerosal--sodium ethyl mercury thiosalicylate, which until recently was used as a preservative in most pediatric vaccines--may have given susceptible children enough mercury to cause autism.
Autism is a profound, poorly understood developmental disorder that severely impairs language and social relations. According to the Centers for Disease Control & Prevention (CDC), autism incidence rose from two to four cases per 10,000 in the 1970s and 1980s to 20 to 60 cases per 10,000 in 2000. Over that period, mercury exposure from thimerosal in vaccines tripled as more pediatric vaccines were developed and the vaccination schedule was made mandatory in many places.
A 1999 report by the California Department of Developmental Services found a 273% increase in autism cases in that state between 1987 and 1998. The observed increase cannot be explained by a broadening in the criteria for diagnosis, says Robert S. Byrd, pediatric epidemiologist at the University of California, Davis.
In 2001, the Institute of Medicine (IOM) issued a report saying that then-current evidence neither proved nor disproved a link between thimerosal in vaccines and autism. But as a precautionary measure, it recommended that exposure to the preservative be reduced. As a result, drug firms removed thimerosal from most pediatric vaccines, but not from the majority of flu vaccines that are given to children as young as six months.
On Feb. 9, researchers presented some of the latest findings on the possible relationship between autism and thimerosal to IOM's Immunization Safety Review Committee. The information they revealed did little to resolve the dispute.
Epidemiologists presented data suggesting that thimerosal in vaccines is harmless. However, toxicologists and a chemist at the meeting discussed findings indicating it is biologically plausible for the doses of thimerosal contained in vaccines to cause autism.
Polly R. Sager, assistant director for international research in infectious diseases at the National Institute of Allergy & Infectious Diseases, noted that during the 1990s, the cumulative exposure to mercury from a typical course of immunizations given during a child's first year was 187.5 µg. On the day of birth, infants usually received 25 µg of mercury from thimerosal in the hepatitis B vaccine. According to Environmental Protection Agency guidelines, a safe level of mercury exposure from food is 0.1 µg per kg of body weight per day, so a vaccine preserved with thimerosal provides far more mercury than the safe intake from food.
Elizabeth Miller, head of the immunization department at the U.K.'s Health Protection Agency, said that medical histories of about 100,000 children born between 1988 and 1997 in the Thames region indicated no connection between exposure to thimerosal and autism. However, the maximum cumulative exposure to mercury from the scheduled vaccines in the U.K. was 75 µg, less than half that in the U.S.
Similarly, Anders P. Hviid, research fellow and biostatistician at the State Serum Institute in Denmark, looked at autism rates and exposure to thimerosal among the 467,450 children born in Denmark from 1990 to 1996. In general, he found no link between thimerosal-containing vaccines and autism. During that period, there were a total of 440 autism cases. The incidence of autism increased throughout the study period as exposure from thimerosal was gradually reduced, he said.
Critics of his study pointed out that the Danish situation is not comparable to that in the U.S. On average, Danish children received less thimerosal during the study period than those in the U.S., and Danish autism rates, even in 1996, were at the same low level as those in the U.S. during the 1980s.
Some experts at the meeting suggested that the only way to establish a link between thimerosal and autism may be to study the children most at risk--boys with a history of neurological problems in the family, for example. The autism rate for boys is four to five times that for girls. And it was noted that it was only through study of an at-risk population that the connection between folic acid and neural tube defects was discovered.
H. Vasken Aposhian, professor of molecular and cellular biology at the University of Arizona, noted that the target organ for thimerosal is the brain and the brains of young children are very sensitive to mercury. He suggested that some children may have difficulty excreting mercury, as evidenced by reduced levels of mercury in the first cut hair from a group of autistic children compared with hair from normal children. "It appears that autistic children lack an effective mercury efflux system," he said. Mercury is excreted in urine, feces, and hair.
Any study of autism should account for the transfer of mercury from mother to fetus, Aposhian said. Recent studies show that the mercury level in the blood of the fetus is about 1.7 times that in the mother, so there is considerable exposure from the mother, he said. Thimerosal in vaccines may provide enough extra mercury to act as a final trigger causing autism, he explained.
Boyd E. Haley, professor of chemistry at the University of Kentucky, agrees. "Autistic children have much lower than average mercury levels in their hair, yet numerous physicians have reported that they carry a higher mercury body burden than control children. There appears to be a subset of the population that cannot excrete mercury and is at greater risk from mercury exposures than the general population," he explained.
Haley said that in vitro studies of neurons in a 50 nM solution of thimerosal show that testosterone speeds up cell death in the solution, while estrogen slows it down. This may explain why the male-female sex ratio for autism is about 4.5 to 1, he said.
AT THE IOM MEETING, Rep. Dave Weldon (R-Fla.), who is a physician, described what he considers to be persecution of researchers investigating vaccine safety. He is receiving many reports from scientists who allege loss of research grants and difficulty in getting papers published when they try to study vaccine safety. "Some [scientists] report overt discouragement, intimidation, and threats, and have abandoned this field of research," he said. "Some have had their clinical privileges revoked, and others have been hounded out of their institutions," he observed.
Weldon alleged that outside researchers have been denied access to post-2000 data in CDC's data set called Vaccine Safety Datalink. They need such data to study the effect of removing thimerosal from the diphtheria, tetanus, and pertussis vaccine in the late 1990s, he said. "It is extremely important that outside, independent investigators be given ample opportunities to review these data sets, and they not be reserved exclusively for government-employed researchers who have conflicts of interest," he said. CDC is tasked with promoting vaccination and monitoring the safety of vaccines, and this creates a conflict of interest, he claimed.
Even if parents decide to avoid thimerosal in vaccines, they may have difficulty finding out which ones contain the preservative. For instance, Aventis Pasteur does not list thimerosal on individual vials or packages of its pediatric flu vaccine. Thimerosal is listed only among the lengthy technical details on the package insert. However, Aventis does manufacture a flu vaccine labeled "preservative-free" on the package.
Parents have filed numerous lawsuits against Aventis and other vaccine manufacturers for alleged harm from thimerosal. Because the topic is under litigation, Aventis will not comment on the issue. The company says in a statement: "We continue to believe that thimerosal-containing vaccines are safe. The Institute of Medicine was very clear in saying that the hypothesis of any danger is not established or supported by either clinical or experimental evidence."
The IOM committee will issue a report in about three months.