Causal association

The subject of what evidence is necessary to conclude that an exposure is causally associated with disease has received much discussion over the years. In 1964, the seminal report to the Surgeon General on Smoking and Health [United States Department of Health, Education, and Welfare (DHEW 1964)] published criteia by which to evaluate whether an exposure was causally related to disease. These criteria were consistency, strength of association, specificity of the association, temporal relationship of the association, and coherence of the association. 

In 1965, Sir Austin Bradford Hill expanded on these criteia in his Environment and Disease Association or Causation (Hill 1965). The article has been widely cited in journal articles, by health risk assessors, and by health risk assessment gnid-ance including that of EPA (2005) and WHO (1999). In his article. Hill described what he referred to as aspects of an association between an environmental exposure and disease that should be considered before detemining that the environmental exposure is causally associated with the disease. These aspects have commonly been referred to as criteria in the Uterature, although Hill nevCT referred to them as such. The aspects that Hill described are  

Consistency. This aspect was described as associations that are repeatedly observed by different pCTsons, in different places, circumstances, and times. HUl also stated, however, that thrae will be occasions when repetition is absent or impossible and a causal association is stiU credible. 

It is important to note HiU s (1965) words on these nine aspects  

Here then are nine different viewpoints flom all of which we should study association before we cry causation. What I do not believe—and this has been suggested—that we can usefully lay down some hard-and-fast rules of evidence that must be obeyed before we can accept cause and effect. None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental question—is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect  

---

Schadt EE, Lamb J, Yang X, Zhu J, Edwards S, Guhathakurta D, et al. An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet 2005 37 710-7. 

Many medications have been implicated (Table 28-1), but a causal association is difficult to confirm because ethical and practical considerations prevent rechallenge. 

Zafirlukast and montelukast are generally well tolerated. Rare elevations in serum aminotransferase concentrations and clinical hepatitis have been reported. An idiosyncratic syndrome similar to the Churg-Strauss syndrome, with marked circulating eosinophilia, heart failure, and associated eosinophilic vasculitis, has been reported in a small number of patients a direct causal association has not been established. 

The primary limiting effect of reserpine is depression. Depletion of central monoamines is believed to be the mechanism for this effect (Heninger et al. 1996 Charney 1998). The depression may occur in a gradual and insidious manner, and the causal association between the drug and depression may be missed (Oates 1996). Rauwolfia alkaloids are contraindicated in anyone with a history of depression, and careful vigilance is required to ensure that they do not induce depression in otherwise normal individuals. Additional side effects are sedation and difficulty with concentration and performing complex mental tasks. 

Scientists skilled in epidemiology, toxicology, and related disciplines collect and evaluate all of the scientific literature containing information regarding the types of toxic effect the chemical under review has been shown to produce. Toxic effects include one or more of the many manifestations of toxicity described earlier in this book. The list of adverse health effects produced by the chemical are said to constitute its toxic hazards, and the critical review and evaluation leading to the list is the hazard identification step. A discussion of the extent to which causal associations with human disease or toxic harm have been established is an important aspect of this step. 

There is sufficient evidence to establish a causal association between human exposure to a substance and the development of cancer. 

Bronchogenic carcinoma and mesothelioma of the pleura and peritoneum are causally associated with asbestos exposure excesses of cancer of the stomach, colon, and rectum have also been observed. Among 632 asbestos workers observed from 1943 to 1967, there... 

Worldwide 5-6 million children die each year of diarrheal diseases. Symptoms of GTI are nausea, vomiting, diarrhea (in case of Shigella and Entamoeba often bloody), abdominal pain and fever. Causal associations have been found between Campylobacter jejuni infections and subsequent Guillain-Barrd syndrome and between enterohem-orrhagic Escherichia coli colitis and the hemolytic uremic syndrome. In severe or complicated cases a faeces culture (and in case of high fever also two blood cultures) should be taken prior to therapy. 

The ATM protein has been identified as an important member of a reaction chain that leads from detection of DNA damage to activation of the p53 protein. Mutations of the ATM protein are causally associated with the disease ataxia telangiectasia, thus the name ATM (ataxia telangiectasia mutated). The ATM protein has protein kinase activity and is counted as a member of the PI3-kinase family, due to sequence homologies (review Canman et al., 1998). The p53 protein is phosphorylated at Serl5 by ATM kinase (Canman et al., 1998) and it is assumed that this phosphorylation contributes to activation of the p53 protein. The ATM protein is preceded by other protein kinases that are directly or indirectly activated by DNA damage and pass this signal on to the p53 protein via the ATM protein. 

The probability that tumours will occur may depend on the species, sex, strain and age of the animal, the dose of the carcinogen and the route and length of exposure. Evidence of an increased incidence of neoplasms with increased level of exposure strengthens the inference of a causal association between the exposure and the development of neoplasms. 

Inadequate evidence of carcinogenicity. The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available. 

Arseneault L, Cannon M, Witten J Murray R (2004). Causal association between cannabis and psychosis examination of the evidence. British Journal of Psychiatry, 184, 110-17... 

Chronic exposure to much lower levels has been associated with leukemia of several types as well as lymphomas, myeloma, and myelodysplastic syndrome. Recent studies have shown the occurrence of leukemia following exposures as low as 2 ppm-years. The pluripotential bone marrow stem cells appear to be a target of benzene or its metabolites and other stem cells may also be targets. Epidemiologic data confirm a causal association between benzene exposure and an increased incidence of leukemia in workers. Most organizations now classify benzene as a known human carcinogen. 

A 2004 report by the Institute of Medicine s Immunization Safety Review Committee concluded that available evidence favored rejection of a causal relation between thimerosal-containing vaccines and autism. In like manner, a recent retrospective cohort study conducted by the CDC did not support a causal association between early prenatal or postnatal exposure to mercury from thimerosal-containing vaccines and neuropsychological functioning later in childhood. 

Two cases of major depression and panic disorder, developing soon after insertion of Norplant and resolving after removal, have been reported, but a causal association was not proven (27). 

Group A Human carcinogens Sufficient evidence from epidemiological studies to support a causal association between exposure to the agents and cancer... 

The general principles of indicators of exposures or effects have not been widely discussed in the literature. Some information is found in WHO, (2001). From the examples mentioned above it appears that indicator or substitute measures are used when exact measurements of effects or exposures are difficult to use for economical, time, or practical constraints. The indicator variable or substitute measure can be any variable with a known (causal or non-causal) association to the variable in question. It should be noted that when causality is established this exposure measure becomes an indicator of the effect and vice versa. In many cases only an association exists and often only within a limited range of exposure situations. 

A review of the case-control studies conducted by the National Cancer Institute, principally on non-Hodgkin s lymphomas, has not established a causal association between atrazine use and the occurrence of this disease (De Roos et al., 2003). This conclusion has also been reached in numerous authoritative reviews (USEPA, 2003a, b International Agency for Research on Cancer (IARC), 1999 United Kingdom (UK), 1996, 2000 Australian Pesticides and Veterinary Medicines Authority (APVMA, 2004). 

---