Causality establishment

Evidence for chemically mediated disruption of thyroid function in wild reptile populations includes the finding of elevated thyroxine levels in male alligators from Lake Apopka, although a causal relationship with specific chemicals has not been established. ... 

To establish the required causal effect of production rate on nitrates a year s history was investigated. For various production rate ranges the percentage of nitrate contents of various magnitudes was tabulated as follows ... 

The events and causal factors chart for this incident is shown in Figure 7.9. The primary sequence of events is shown horizontally in bold boxes. Secondary events are shown in the other boxes, and conditions are in ovals. From the diagram three causal factors were identified and carried forward to the Root Cause Coding to establish the root causes of the causal factors. 

Atmospheric exposure trials, carried out in Cambridge, established the fact that when rusty specimens were painted in the summer, their condition, after some years exposure, was very much better than that of similar specimens painted in the winter It was found that steel weathered in Cambridge carried spots of ferrous sulphate, deeply imbedded in the rust, and that the quantity of ferrous sulphate/unit area was very much greater in the winter than in the summer this seasonal variation was attributed to the increased sulphur dioxide pollution of the atmosphere in the winter, caused by the combustion of coal in open grates. It was concluded that there was a causal relationship between the quantity of ferrous sulphate and the effective life of the paint. It was suggested that these soluble deposits of ferrous sulphate short-circuit the resistance of the paint film and, since paint films are very permeable to water and oxygen, the ferrous sulphate will become oxidised and hydrolysed with the production of voluminous rust, which will rupture the film at numerous points, thus giving rise to the characteristic type of failure seen on painted rusty surfaces. 

For future research in this field, in addition to physiological and biochemical approaches, genetic analysis will be essential in the establishment of causal relationships between the induction of a stress protein and the establishment of tolerance to the stress condition. In most cases it is not difficult to detect the induction of new proteins during stress. However, the induction of new proteins does not necessarily establish stress tolerance it may well be the consequence of damage caused by stress conditions. Thus, genetic mutants will be necessary to test the physiological role of a stress protein. 

The origin of the observed correlation was not established, and the relation was not interpreted as causal. It could be argued that a sustained elevated potential due to as-yet unknown microbial processes altered the passive film characteristics, as is known to occur for metals polarized at anodic potentials. If these conditions thickened the oxide film or decreased the dielectric constant to the point where passive film capacitance was on the order of double-layer capacitance (Cji), the series equivalent oxide would have begun to reflect the contribution from the oxide. In this scenario, decreased C would have appeared as a consequence of sustained elevated potential. 

Adams S. 2003. Establishing causality between environmental stressors and effects on aquatic environments. Human Environ Risk Assess 9 17-35. 

Male patients with RA must receive counseling about the effects of certain medications on their fertility and potential harm to the fetus. It is difficult to establish causality between use of a medication by a male and the effect on fertility or fetal development therefore, a conservative approach must be taken. Patients of childbearing potential and their partners must be counseled to (1) use proper birth control while undergoing treatment for RA and (2) discontinue medications at least 3 months before conception.37... 

The risk of gout increases as the serum uric acid concentration increases, and approximately 30% of patients with levels greater than 10 mg/dL (greater than 595 pmol/L) develop symptoms of gout within 5 years. However, most patients with hyperuricemia are asymptomatic. Other risk factors for gout include obesity, ethanol use, and dyslipidemia. Gout is seen frequently in patients with type 2 diabetes mellitus and coronary artery disease, but a causal relationship has not been established. 

Ideally, to establish a causal relationship between caffeine and improved athletic performance, evidence would be obtained from epidemiological population studies, followed by careful, double-blind, placebo controlled experimental protocols isolating the purported etiological agent (caffeine), and eventually culminating with strong laboratory findings... 

In addition to the classical stress hormones already reviewed, several other hormones are augmented in response to stress. Stress-induced prolactin release is one of the most frequently studied examples. There is no doubt about the causal relationship between stress and increased pituitary prolactin release, but the biological meaning is much less clear (G2). This phylogenetically old hormone has been shown to have more than 85 different functions in all vertebrate species. However, besides its role in the induction of maternal lactogenesis, the physiological importance of prolactin is at present not fully established. Experimental and clinical evidence supports the view that prolactin is also an immunoregulating hormone (M44, R18). Prolactin receptors are present on human T and B lymphocytes (R18), and T lymphocytes depend on prolactin for maintenance of immunocompetence (B19). In addition, it has been shown that prolactin is able to influence the devel-... 

The wide gap between the two opposing theories, replication first and metabolism first , was analysed by Pross from the Ben Gurion University of the Negev (Israel). Pross concludes that replication came first He is convinced that a causality between the two theories can only be established if it is assumed that the replication-first thesis is correct. His analysis also shows that more of the experimental results and theoretical rationales favour the replication thesis. The author finds his assumption justified that life processes are strongly kinetically controlled and that the development of metabolic pathways can only be understood if life is considered as a manifestation of replicative chemistry (Pross, 2004). 

In the 12-month safety study (N = 805, 2 1 (alvimopan placebo) randomization) 3 at 0.5 mg twice daily was well tolerated and showed evidence of sustained efficacy when taken continuously for 12 months by patients with nonmalignant pain requiring sustained treatment with opioids. However, unexpectedly, there were more reports of myocardial infarctions in patients treated with 3 at 0.5 mg twice daily compared with placebo-treated patients. The majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of 3, including studies in patients undergoing bowel resection surgery who received 3 at 12 mg twice daily for up to 7 days. A causal relationship with 3 has not been established [29]. 

In order to establish a causal relationship rather than a pure association between the suspected carcinogen Rn-d and the induced effect lung cancer it is most important to know the individual Rn-d exposure. This is the particular weakness of all these studies since these measurements were not carried out fifteen to thirty years ago, this essential information cannot be provided by any of the available retrospective studies with a sufficient degree of reliability and accuracy (Steinhausler, in press). Therefore they have to rely on indirect estimation of past Rn-d exposure levels, using e.g. inference from uranium ore content. 

Nitrosoarenes are readily formed by the oxidation of primary N-hydroxy arylamines and several mechanisms appear to be involved. These include 1) the metal-catalyzed oxidation/reduction to nitrosoarenes, azoxyarenes and arylamines (144) 2) the 02-dependent, metal-catalyzed oxidation to nitrosoarenes (145) 3) the 02-dependent, hemoglobin-mediated co-oxidation to nitrosoarenes and methe-moglobin (146) and 4) the 0 2-dependent conversion of N-hydroxy arylamines to nitrosoarenes, nitrosophenols and nitroarenes (147,148). Each of these processes can involve intermediate nitroxide radicals, superoxide anion radicals, hydrogen peroxide and hydroxyl radicals, all of which have been observed in model systems (149,151). Although these radicals are electrophilic and have been suggested to result in DNA damage (151,152), a causal relationship has not yet been established. Nitrosoarenes, on the other hand, are readily formed in in vitro metabolic incubations (2,153) and have been shown to react covalently with lipids (154), proteins (28,155) and GSH (17,156-159). Nitrosoarenes are also readily reduced to N-hydroxy arylamines by ascorbic acid (17,160) and by reduced pyridine nucleotides (9,161). 

Rosiglitazone has been associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction in several studies. Although causality has not been conclusively established, the FDA has required that a black box warning be added to the labeling. A new longterm study to evaluate potential cardiovascular risks is planned. 

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. 

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