National Acetaminophen Sales and Autistic Disorder in California


                                                          Stephen Schultz 2006

reposted from <http://pwp.att.net/p/s/community.

dll?ep=16&groupid=389714&ck=>


 
 

Schultz compared published annual national sales of children’s acetaminophen and aspirin products between 1979 and 1985 by Arrowsmith with the number of children with autistic disorders (AD) reported by the California Department of Developmental Services (DDS). Abstracting data from a graph by Arrowsmith et al. Schultz determined the number of children’s aspirin tablets, acetaminophen tablets, and cubic centimeters of acetaminophen liquid sold in the U.S. from 1979 to 1985. Data on eligible individuals by year of birth was abstracted from a figure in the 1999 report to the legislature by the California DDS — reporting data collected by 21 regional centers providing services to these children. Estimates indicate that 75-80% of eligible parents register with the DDS. These data were used to perform two linear regressions. The first regression included individuals born from 1961-1980; the second included individuals born from 1980-1990. The slopes of the two lines were compared to determine whether a significant change occurred in the incidence of autism after sales of children’s aspirin decreased and sales of children’s acetaminophen products increased in 1980 (figure 1).


ABSTRACT


Objectives: This study was performed to determine whether trends in national sales of children's aspirin and acetaminophen products were associated with trends in reported cases of autistic disorder.

Methods: This is an ecologic study using published annual national sales of children’s acetaminophen and aspirin products between 1979 and 1985 and the number of children with autistic disorder eligible for services from the California Department of Developmental Services.

Results: There was a marked decline in children’s aspirin sales and concomitant rise in sales of children’s acetaminophen products beginning in 1980, which corresponded to an increase in children with autistic disorder eligible for services in California. Based on linear regression, annual sales of children’s acetaminophen tablets and liquid showed significant positive associations with cases of autistic disorder by year of birth (p<0.05), while sales of children’s aspirin products showed a significant negative association (p<0.01).

Conclusions: Decreased national sales of children’s aspirin and increased sales of children’s acetaminophen were significantly associated with an increased number of children with autistic disorder eligible for services in California. These data suggest a possible link between acetaminophen sales and autistic disorder.


INTRODUCTION


Autistic disorder (AD) is a severe developmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that appear in early childhood.[1] There is a strong genetic component to AD with a reported rate of 60 percent concordance in monozygotic twins.[2] AD can be comorbid with tuberous sclerosis (1.2%), fragile X syndrome (0.3%), and congenital rubella syndrome (0.3%), although the attributable proportion of all medical disorders is less than 10% [3] In most cases the cause of AD is unknown.[3]


A report from the California Department of Developmental Services (DDS) [4] shows a marked increase in the number of individuals with AD who are eligible for services. This report shows the number of persons with AD increased in their client population from 2,778 to 20,377 for the years 1987 to 2002. As a percent of their total client population, AD increased from 3.5 percent to 12.4 percent during this period. The reason for this increase is unclear and may not indicate an increase in AD incidence since changing case definitions, administrative procedures, and service issues have had an effect on the number of individuals with AD eligible for services in California and nationwide.[5]


There are several theories about possible environmental triggers for AD including childhood vaccinations, mercury exposure, and viral infections. Descriptive clinical studies have suggested a link between measles-mumps-rubella (MMR) vaccination and AD/pervasive developmental disorder.[6-12] Epidemiological studies have not supported the relationship between prevalence of autism and the MMR vaccine.[13] A 14-year prospective study of children from Finland showed no association between the MMR vaccination and AD.[14] Two large population studies from Denmark and England also showed no epidemiological evidence for association.[15,16] An ecological study from England found no significant increase in AD following the introduction of the MMR vaccination [17], and comparison of MMR vaccination coverage in California with the increasing autism trend from the California DDS also showed no association.[18]


While the link between the MMR vaccine and an elevated risk of AD is controversial, it is possible that some factor temporally related to the MMR vaccination increases the risk for AD in some children. Children are often given acetaminophen if they have symptoms such as fever or irritability, and the MMR vaccination can cause these symptoms. Perhaps the administration of acetaminophen is associated with the development of AD in these children.


Our previous case-control study is the only investigation that has shown a link between acetaminophen use and AD.[19] However, a pilot study of low functioning children with AD indicated that some children had a sulfation deficit which causes them to process acetaminophen differently from the control group.[20]


There are three pathways for the metabolism of acetaminophen: glucuronidation, sulfation, and the cytochrome P-450 system. In children, sulfation is the primary pathway for acetaminophen metabolism until age 10-12 years.[21] With a sulfation deficit, more acetaminophen could be metabolized by the cytochrome P-450 system which would increase production of the toxic metabolite N-acetyl-pbenzoquinone imine (NAPQI), a known immune system inhibitor.[22] Normally, when NAPQI is produced, it is conjugated with glutathione and excreted as non-toxic conjugates. One study found that children with AD had significantly lower plasma levels of glutathione than the control group.[23] The possible model for the relationship of acetaminophen to AD is a buildup of NAPQI which in theory could be an environmental trigger for AD.


The present study was performed to determine if national sales patterns of acetaminophen could be associated with the number of individuals with AD who were eligible for services from the California DDS.


METHODS


An internet search revealed four historical events in the history of acetaminophen. These events were compared with the number of eligible persons with AD from a 1999 report to the legislature by the California DDS.[24] This data was collected by 21 regional centers that provide services to children with developmental disabilities. Because this report only contains information on children whose parents had registered for assistance, it is not a complete ascertainment of all cases. However, it is estimated that 75-80% of parents have registered based on electronic linkage of California’s DDS database with the Department of Education, special education databases.[25]


The number of eligible persons with AD by year of birth was abstracted from Figure 1 in the California report.[24] This information was used to perform the first analysis consisting of two linear regressions to determine if there was a change in the AD trend before and after the publication of a link to Reye Syndrome from aspirin use.[26] The first linear regression included individuals born from 1961-1980 and the second linear regression included individuals born in 1980-1990. The slopes of the two lines were compared to indicate whether a significant change occurred in the AD trend after the sales of children’s aspirin decreased and the sales of children’s acetaminophen products increased in 1980.[27]


For the second analysis, information on analgesic sales was abstracted from the graph in a published manuscript by Arrowsmith and colleagues.[27] (Original data was unavailable.) This yielded the number of children’s aspirin tablets, acetaminophen tablets, and cubic centimeters of acetaminophen liquid sold in the US for the years 1979-1985. Linear regression models were developed to determine if annual sales of children’s aspirin or acetaminophen products were associated with year of birth for eligible individuals with AD in California.


RESULTS


Figure 1 shows the number of eligible persons with AD by year of birth adapted from the 1999 report to the legislature by the California DDS.[24] The figure shows a notable increase in the number of eligible persons with AD born after 1980. Superimposed on the figure are events in the history of acetaminophen. In 1977 a Food and Drug Administration (FDA) panel recommended a warning label be placed on acetaminophen products due to the association of acetaminophen use and liver damage.[28] This corresponds to a drop in the number of eligible individuals with AD for a birth year of 1977.


As previously detailed, there was an increase in acetaminophen sales beginning in 1980, which corresponds to an increasing trend in the number of eligible individuals with AD born after 1980. In 1982 and again in 1986, acetaminophen capsules were tampered with by replacing the contents with cyanide. Seven people were killed in Chicago when they ingested the cyanide-laced acetaminophen capsules in 1982.[29] One woman was killed in New York when she ingested cyanide-laced acetaminophen capsules in 1986.[30] Both of these events precipitated sharp declines in acetaminophen sales. Correspondingly, there are inflections in the increasing AD trend in the number of eligible individuals for the years 1982-1984 and 1986-1987.


As shown in Table 1, regression coefficients for the number of eligible individuals with AD were significantly different for those born between 1961-1980 and 1980-1990 (t test, p<.0001). In other words, there is a significant difference in the slope of the AD trend in California before and after 1980. Linear regression was also performed to determine if sales of children’s analgesics were related to the number of enrolled individuals with AD in California by birth year. These analyses were adjusted for population growth in California.[31] The sales of children’s aspirin products showed a significant negative association with the number of individuals with AD (p<0.01). Both sales of children’s acetaminophen tablets and liquid showed significant positive associations with AD (p<0.05). The results of these linear regressions are shown in Table 1.


DISCUSSION


The sales of children’s aspirin products declined and the sales of children’s acetaminophen products rose after an aspirin-Reye Syndrome link was reported in 1980.[26] Using data abstracted from the report by the California DDS [24], the increasing trend of AD cases for the period after 1980 was significantly greater than for the period before 1980. This significant difference could be due to increasing sales of children’s acetaminophen products which would presumably lead to more use by young children.


However, the changing trend in AD registration in California may be due to many other factors and does not necessarily indicate an increase in AD incidence. Better diagnosing of AD or the increased availability of services may have caused an increase in registration. The diagnosis of AD has changed over time. The third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), published in 1980, separated the diagnosis of autism from childhood schizophrenia and placed it under a new category of pervasive developmental disorders.[32] DSM III criteria included onset before 30 months of age, lack of responsiveness to other people, gross impairments in communication and language, and bizarre responses to the environment. DSM IV, published in 1994, defines autism as part of a spectrum of disorders with variations in severity.[1] Communication difficulties are the primary differences in the criteria for the autistic spectrum disorders, which include autistic disorder, Asperger's disorder, and pervasive developmental disorder-not otherwise specified.[1]


A world-wide review by Fombonne of autism epidemiological surveys concluded that changes in case definition and improved awareness account for much of the increased autism trend in recent decades.[33] A further report by Chakrabarti and Fombonne reported a stable incidence in Midlands, UK over 15 years when study design features were held constant.[13] Further study is needed to establish whether there has been a true increase in autism incidence world-wide and/or in California.


In 1969, the Lanterman Mental Retardation Services Act established regional centers of care in California for persons with mental retardation. In 1973 this act was amended to include persons with autism and other developmental disabilities, and in 1976 this act was again amended to establish a right to treatment and habilitation services for children and adults with developmental disabilities.[34] The availability of these services may have contributed to the increasing trend in the number of eligible individuals with AD who were registered in California.


Linear regression of national sales of children’s aspirin tablets, acetaminophen tablets, and acetaminophen liquid with the number of eligible individuals with AD in California yielded significant associations. Sales of children’s aspirin decreased and sales of children’s acetaminophen increased as AD increased. The increasing AD trend in California may be related to increasing use of children’s

acetaminophen or decreasing use of children’s aspirin. Although these events may be related, it is also possible that these are coincidental findings and that AD has no relation to changing analgesic sales.


The linear regression analysis of analgesic sales with AD cases is problematic. National children’s analgesic sales were abstracted from a graph in a published study.[27] Although the principal investigator of this study was contacted, the raw data for this graph was no longer available. No national figures for the numbers of individuals with AD were available for the study years, and this study relied on the number of individuals with AD abstracted from a California report.24 Further, although sales of children’s analgesics vary from year to year, the observations are not independent, and sales from any given year will be correlated with sales from the previous year. This correlation could lead to errors in a linear regression analysis but should have been suitable for this preliminary study.


For each of four historical events related to acetaminophen, there is a corresponding inflection in the number of eligible individuals with AD in California as shown in figure 1. These inflections would be expected if acetaminophen exposure is related to development of AD. However, the drop in the number of individuals with a birth year of 1977 could be an artifact since it occurred in only one year. Also, the increase in the trend for AD that began in 1980 could be due to other factors as previously detailed. More interesting are the apparent effects of historical events in 1982 and 1986 when eight people were murdered with cyanide-laced acetaminophen capsules. The apparent effects from both of these events (from the graph in Figure 1) continued for more than one year and precipitated declines in an AD trend that had been increasing and which afterwards continued increasing after 1987 through 2002.[4] Of course, other events could be responsible for the decreases in the number of eligible individuals with those birth years.


Other environmental factors may also be involved in the apparent increase in AD seen in this study. For example, low levels of breastfeeding could decrease immune protection in infants by decreasing mother to child transfer of IgA. Decreased immune protection could make a child more vulnerable to viral infection which in theory could lead to AD. The prevalence of breastfeeding in the US increased during the 1970s and decreased during the 1980s.[35] This pattern does not correlate well to the reported cases of AD seen in the present study but has in the authors’ previous work.[36]


The significant differences seen in this study should be viewed with caution, as this is an ecological study with no measured acetaminophen exposures in any of the individuals with AD. The purpose of this study was to explore a possible correlation between acetaminophen sales and AD. The authors have further explored this possible relationship in a case-control study and have found a significant difference in acetaminophen use in those with and without AD.[19] The authors hope that this report is followed by additional case-control and cohort studies to confirm these findings.


Acknowledgments

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. The principle investigator has reviewed all data reported in this article.


References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th ed. Washington (DC): American Psychiatric Association; 1994.

2. Bailey A, Le Couteur A, Gottesman I, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995;25:63-77.

3. Fombonne E. Epidemiological surveys of autism and other pervasive developmental disorders: an update. J Autism Dev Disord 2003;33(4):365-82.

4. Department of Developmental Services, California Health and Human Services Agency. (2003). Autistic Spectrum Disorders—Changes in the California Caseload. An Update: 1999-2002.

5. Mandell DS, Palmer R. Differences Among States in the Identification of Autistic Spectrum Disorders. Arch Pediatr Adolesc Med 2005;159:266-269.

6. Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351:637-641.

7. Singh VK, Lin SX, Newell E, Nelson C. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci 2002;9(4):359-64.

8. Singh VK, Jensen RL. Elevated levels of measles antibodies in children with autism. Pediatr Neurol 2003;28(4):292-4.

9. Kawashima H, Mori T, Kashiwagi Y, Takekuma K, Hoshika A, Wakefield A. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci 2000;45(4):723-9.

10. Uhlmann V, Martin CM, Sheils O, et al. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Mol Pathol 2002;55(2):84-90.

11. Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S, et al. Enterocolitis in children with developmental disorders. Am J Gastroenterol 2000;95(9):2285-95.

12. Furlano RI, Anthony A, Day R, Brown A, McGarvey L, Thomson MA, et al. Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr 2001;138(3): 366-72.

13. Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool children: confirmation of high prevalence. Am J Psychiatry 2005;162(6):1133-1141.

14. Peltola H, Patja A, Leinikki P, Valle M, Davidkin I, Paunio M. No evidence for measles, mumps, and rubella vaccine-associated inflammatory bowel disease or autism in a 14-year prospective study. Lancet 1998;351:1327-1328.

15. Taylor B, Miller E, Farrington P, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999;353:2026-2029.

16. Madsen KM, Hviid A, Vestergaard M, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002;347(19):1477-1482.

17. Chen W, Landau S, Sham P, Fombonne E. No evidence for links between autism, MMR and measles virus. Psychol Med 2004;34:543-53.

18. Dales L, Hammer SJ, Smith NJ. Time trends in autism and MMR immunization coverage in California. JAMA 2001;285(9):1183-5.

19. Schultz S.T., Klonoff-Cohen H.S., Wingard D.L., Akshoomoff N.A., Macera C.A., & Ji M. Acetaminophen after Measles-Mumps-Rubella Vaccination and Autistic Disorder: The Results of a Parent Survey. Autism 2008;12(3):293-307.

20. Alberti A, Pirrone P, Elia M, Waring RH, Romano C. Sulphation deficit in “low-functioning” autistic children: a pilot study. Biol Psychiatry 1999;46:420-4.

21. Tucker, J. Toxicity, Acetaminophen. <http://www.emedicine.com/ped/topic7.htm> Accessed November 7, 2005.

22. Senter PD, Al-Abed Y, Metz CN, et al. (2002) Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites. Proc Natl Acad Sci USA 2002;99(1):144-9.

23. James SJ, Cutler P, Melnyk S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004;80(6):1611-7.

24. Department of Developmental Services, California Health and Human Services Agency. Changes in the population of persons with autism and pervasive developmental disorders in California’s Developmental Services System: 1987 through 1998. A Report to the Legislature March 1, 1999.

25. Croen LA, Grether JK, Hoogstrate J, Selvin S. The changing prevalence of autism in California. J Autism Dev Disord 2002;32(3):207-215.

26. Starko KM, Ray CG, Dominguez LB, Stromberg WL, Woodall DF. Reye's syndrome and salicylate use. Pediatrics 1980;66(6):859- 864.

27. Arrowsmith JB, Kennedy DL, Kuritsky JN, Faich GA. National patterns of aspirin use and Reye Syndrome reporting, United States, 1980 to 1985. Pediatrics 1987;79(6):858-63.

28. <http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3882T1.htm> Accessed November 7, 2005.

29. Beck M, Monroe S, Prout L, Hager M. LaBreque R. The Tylenol Scare. Newsweek magazine, October 11, 1982.

30. Koepp S. A hard decision to swallow. Acetaminophen’s maker will dump capsules and promote safer “caplets”. Time magazine, March 3, 1986.

31. Department of Finance, California (2006). Retrieved June 29, 2006 from http://www.dof.ca.gov

32. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington (DC): American Psychiatric Association; 1980.

33. Fombonne E. Epidemiological surveys of autism and other pervasive developmental disorders: an update. J Autism Dev Disord 2003;33(4):365-82.

34. Department of Developmental Services, California (2006). Retrieved February 10, 2006, from <http://www.dds.cahwnet.gov>

35. Mothers Survey, Ross Products Division, Abbott Laboratories 2002.

  1. 36.Schultz S.T., Klonoff-Cohen H.S., Wingard D.L., Akshoomoff N.A., Macera C.A., Ji M., & Bacher C. Breastfeeding, infant formula supplementation, and autistic disorder: the results of a parent survey Int Breastfeed J 2006;15;1:16.


Figure 1 shows a significant difference in the slope of the autism trend in California between those born from 1961 to 1980 and from 1980 to 1990. The number of eligible persons with autistic disorders born after 1980 increased considerably. Decreased nationwide sales of children’s aspirin and increased sales of children’s acetaminophen beginning 1980 were significantly associated with a greater number of children with autistic disorders eligible for services in California. Superimposed on the figure are other revealing events in the history of acetaminophen. In 1977 a Food and Drug Administration (FDA) panel recommended a warning label be placed on acetaminophen products because of their propensity to damage the liver. Fewer children with AD were born in 1977. In 1982 seven people died after ingesting Tylenol capsules laced with cyanide; in 1986 one person died after ingesting Tylenol capsules similarly tampered with. These events precipitated sharp declines in acetaminophen sales, and parallel declines in the number of children with autistic disorders in California from 1982-1984 and 1986-1987.


Figure 1. Number of enrolled persons with autistic disorder in California by year of birth, and critical events in the history of acetaminophen.