modifying the effect of light on circadian rhythmicity . It is ecoming apparent that timing of meals and alcohol gestion can alter circadian rhythms independently of light nd also affect light ’ s ability to phase shift circadian hythms . These ideas may have relevance to risk of breast ancer in women in the industrialized world . For those omen on non-day shift work schedules , the timing and omposition of meals may be an important co-factor in eir risk of breast cancer [ 28 ]. Change in time of day of meals in rats can uncouple the rcadian rhythm of the liver from that in the SCN [ 57 ]. hanges in circadian markers occur less rapidly in other ssues such as kidney , heart , and pancreas than in the liver 8 ], but eventually also become uncoupled from the SCN . aird et al . [ 59 ] reported on experiments in which rats ceived ethanol injections at four times during the day : am , 7 am , 1 pm , and 7 pm . Ethanol shifted circadian ctivity and temperature rhythms depending on the time it as administered . Earnest and colleagues have been investigating the efcts of developmental exposure to ethanol in rats . They ave found that ethanol during the period of rapid brain evelopment ( postnatal days four to nine ) causes permaent changes in the endogenous circadian clock of the SCN 60 ]. In particular , rats exposed to ethanol at ages four to ne days postnatal ( corresponding to third trimester utero exposures in humans ), are more sensitivity to the hase shifting effects of a light pulse during the dark period f the circadian day [ 61 ]. Moderate to heavy alcohol onsumption has been consistently associated with inreased risk of breast cancer in women [ 62 ]. Stevens and iatt [ 63 ] suggested that alcohol ingestion may result in wered melatonin levels which , in turn , may lead to eleated circulating estradiol concentration in blood [ 16 ]. tevens and Hilakivi-Clarke [ 64 ] hypothesized that expoure of pregnant rats to ethanol would increase susceptility to mammary tumorigenesis in their female offspring y raising estradiol . Hilakivi-Clarke et al . [ 65 ] have now vestigated this possibility . Pregnant female Sprague – awley rats were pair-fed isocaloric diets containing either 6 % alcohol of total energy ( labeled as low ), 25 % alcohol moderate ) or no alcohol , from day seven to day 19 of regnancy . These alcohol exposures generate blood alcohol vels of about 61 mg / dl ( 0.061 %, stimulatory dose ) and 6 mg / dl ( 0.096 %, modestly intoxicating dose ), respecvely , and are much lower than those that induce fetal cohol syndrome in rodent models ( which is between 15 % and 0.175 %). Female rats exposed to alcohol utero developed increased number of mammary tumors , onsistent with increased presence of terminal end buds nd epithelial density seen in these animals . The greatest mor yield and greatest mammary density in the female ffspring at their adulthood was in the moderate in utero alcohol group . However , for estradiol , there was an in crease in pregnant rats in the lower alcohol group , but not in the moderate alcohol group . This casts doubt on the presumed estradiol-mediated mechanism for an in utero alcohol effect on mammary tissue development and breast tumorigenesis , and may indicate a role for altered circadian functioning as a mechanism .
For breast cancer in women , and the potential for exposures of pregnant women to increase risk in their daughters later in life , the role of diet and alcohol in modifying circadian rhythms and interacting with lighting is an important area of pursuit .
Early susceptibility and lifelong risk
If cancer requires two or more mutations in a cell [ 66 , 67 ] as is currently believed , then the occurrence of breast cancer at a young age does not require membership in a susceptible subgroup . There will be a distribution of cases across the age spectrum even if all women were genetically identical and had similar carcinogen exposures throughout life . However , there clearly are susceptible subgroups who are indeed diagnosed with breast cancer at a younger age such as carriers of a mutant BRCA1 allele . Mutations in genes involved in fundamental processes of cell cycle regulation and apoptosis would be expected to be more strongly associated with risk in young women because these processes begin at conception . Given the emerging realization of the central role of the clock gene apparatus in gene regulation throughout the organism , there may be specific clock gene variants which also confer early susceptibility . These may both explain part of the family history effect from germ line mutation , and confer increased individual risk from sporadic mutation . In support of this possibility , Zhu et al . [ 68 ] have reported that a polymorphic variant of the Per3 gene is associated with breast cancer in young women .
Causal associations and biological mechanisms
There are two pathways to discovering causal associations : serendipity and prediction . The vast majority of causal associations have been found by the first pathway , serendipity . This has come from the astute observation of a series of cases , from ecological studies , and from large epidemiological studies examining many exposures . For example , it became clear from epidemiology that smoking ‘ caused ’ ( i . e ., greatly increased risk ) lung cancer long before biological mechanisms were identified . There is now consensus that the observed association of smoking and lung cancer in epidemiological studies is causal ; yet ere is still not consensus on exactly what mechanism ( s ) operating . Many examples of this exist including conensus that the associations of HBV and liver cancer , spirin use and colon cancer , and alcohol and breast ancer are all causal , yet for none of these is there conensus on what is the dominant mechanism . For each , much has been learned about the pathophysiology of xposure to the agent , but it is still not clear what part of is pathophysiology is most important , or whether there re other unrecognized mechanisms which account for the bserved causal association . To obtain consensus that an observed association is ausal requires more epidemiogical studies to eliminate hance , and then bias , as accounting for the results . At ome point , it becomes clear that the exposure ‘ causes ’ the sease . Factors to consider are described by Hill [ 69 ] and clude strength , consistency , dose response , reversibility , oherence , temporality , and biological plausibility . Biogical plausibility , or lack of it , is weak evidence for or gainst the causality of an association ; as Hill wrote : … this is a feature we cannot demand .’ Strength of the association is only pertinent to a judgment of causality , not of importance . Once an association is dged to be causal , then even a very modest relative risk an be very important . For example , smoking accounts for more deaths from heart disease than from lung cancer depite the fact that the relative risk is over ten for lung ancer but less than two for heart disease . The shift work association with breast cancer was found nly after a biological mechanism was proposed and a rediction made ( by letter to the Nurses ’ Health Study in 987 , and then published in 1992 ; 5 ). Before this associion can be judged to be causal , chance and bias must be iminated as plausible explanations . The status of this ssociation is shown below . It is rare for a postulated biological mechanism to lead an epidemiological observation , as was the case for shift ork and breast cancer . More typically , the epidemiologal observation is made and then this leads to laboratory / asic science aimed at identification of potential biological mechanisms .
eason for bserved association
hance ias ausal
Status of evidence
Biological plausibility plays at best a minor role in dging causality , and is not required . The value in identifying purpos by wh interve howev helpful away . anism dence
The causal , nism . P mecha this co reality ,
Conclu
The to cancer years . night melato mecha emerge the or
Too few studies so far conducted to eliminate chance despite ‘ significance ’ of some of them Other factors associated with shift work may be the real cause , e . g ., alcohol consumption If chance and bias are eliminated , then the association is causal
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Page A- 76 White Paper – Communities Addressing Light Pollution that Af