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benefit was greater in historical studies . For example , the 2007 systematic review59 of studies reported since 1966 estimated an overall relative difference of one third , whereas most of the subsequent studies summarized in Table 5 report smaller relative differences . Also , as seen in studies of children , the systematic review in adults59 used more inclusive selection criteria than the 2015 Cochrane systematic review which also included studies of adults, but which concluded that " no studies that aimed to determine the effectiveness of water fluoridation for preventing caries in adults met the review' s inclusion criteria " .43 Some studies of adults distinguish between preventive benefits from exposure in childhood and in adulthood , suggesting that both periods of exposure are important . Consistently, though , the studies reviewed in Table 5 conclude that lifetime exposure to fluoridation confers the greatest caries- preventive benefit . This finding is considered in further detail in the next section, which reviews hypothesized biological mechanisms underlying the preventive benefits observed in association studies . 2 . 3. 9 Causal inference and biological mechanisms of action There are well -established criteria to evaluate whether or not an association between exposure and disease is causal . For example , when judging the health effects of smoking ( which , on ethical grounds, can never be tested in an experimental study of humans ) , the 2004 U . S . Surgeon General ' s Report60 applied seven criteria . Those criteria as they apply to caries- preventive benefits of water fluoridation are reviewed briefly below . 1 . Consistency: results from association studies should be replicated in different studies and populations. As reviewed above, systematic reviews from studies spanning more than half a century and conducted in multiple countries are consistent in concluding that exposure to water fluoridation is associated with lower levels of dental caries in children . 2 . Strength of association : a greater magnitude of effect suggests an association that is more likely causal. The first association studies, conducted at a time when dental caries was rampant, and when fluoride was available only in drinking water demonstrated profound reductions in dental caries experience associated with lifetime exposure to fluoridation . 3 . Specificity : the exposure should be associated with only one or a few diseases. While fluoridation has been investigated for potential preventive effects in other oral diseases ( including gingivitis and periodontal disease ) , no association was found . 4 . Temporality: exposure to the putative cause should precede development of the disease. As noted in above , this criterion is satisfied in studies that measure lifetime caries experience in lifetime residents of either fluoridated or non -fluoridated areas . 5 . Biological gradient: incremental effects on disease are observed with incrementally greater exposure This was demonstrated first in Dean ' s " 21 - cities " study, 32 where the concentration of fluoride varied , and has 1 The Surgeon General ' s report gives least credence to the specificity criterion when evaluating chronic diseases, noting that its existence can strengthen a causal claim , but its absence does not weaken it .