endogenous nitrosation in relation to nitrate exposure from ......endogenous nitrosation in relation...

[CANCER RESEARCH 49, 3117-3121, June 1, 1989]

Endogenous Nitrosation in Relation to Nitrate Exposure from Drinking Water and

Diet in a Danish Rural PopulationHenrik Moller,' Jannik Landt, Erling Pedersen, Per Jensen, Herman Autrup, and Ole Mrtllcr Jensen

Danish Cancer Society, Danish Cancer Registry, Institute of Cancer Epidemiology, Rosenvaengets Hovedvej 35, P. O. Box 839, DK-2100, Copenhagen [H. M., O. M.J.], Danish Cancer Society, The Fibiger Institute, Copenhagen fJ. L., H, A.], National Food Agency, Stborg [E. P.], Institution of Medical Health Officers,Nordjyllands Amt [P. J.], Denmark

ABSTRACT

Increasing levels of nitrate in drinking water is of concern due to thepossibility of an associated increase in long-term exposure to endoge-nously formed carcinogenic A-nitroso compounds. Excretion of .V-nitro-soproline in 12-h overnight urine after intake of 500-mg L-proline wasused to quantify the rate of endogenous nitrosation in 285 individuals inan area in northern Denmark with large variation in nitrate concentrationof the drinking water. Nitrate intake was measured in a 24-h duplicatediet sample. The crude association between nitrate concentration indrinking water and rate of endogenous nitrosation in individuals is onlyweakly positive and not quite statistically significant (/' = 0.08). The risk

of having detectable nitrosation increases significantly with total nitrateintake and tobacco smoking. In nonsmokers, nitrosation is determined bynitrate intake. Smokers have increased nitrosation which does not dependon nitrate intake. Effect modification through dietary factors was evaluated and indicated a protective effect of tea consumption, while the effectof eating vegetables was not clear-cut. The experimental design (12-hurine sample; proline dose taken in the evening) is likely to underestimatethe effect of nitrate in drinking water relatively to nitrate in the diet.

INTRODUCTION

The average concentration of nitrate (NOj) in ground waterused as drinking water in Denmark increased from 3.0 mgNOj/liter to 13.3 mg/liter over the period 1940 to 1983 (1).The maximum nitrate concentration in Denmark should notexceed 50 mg/liter and it is recommended that water with morethan 25 mg/liter is not used as drinking water. However, by1983 some 6-7% of the Danish population had water supplieswith more than 50 mg/liter, and 13-14% used water with morethan 25 mg/liter (1). Health hazards related to a high intake ofnitrate include the rare, acute toxic effect methaemoglobinae-mia in bottle-fed infants (2), and the possibility of increasedexposure to endogenously formed carcinogenic Â¿V-nitrosocompounds (3-8). I has been suggested that gastric cancer is associated with nitrate intake through this mechanism (9-15), although the more recent evidence, especially from Britain, donot show this association (16-19).

In a previous paper we demonstrated that drinking watermay be a major source of total nitrate intake (20). With 50 mgnitrate per liter drinking water, the average Danish consumeris exposed to 90 mg nitrate per day, more than half of which isderived from the drinking water. Consumption of vegetables isthe other important source of nitrate and provides on averageabout 40 mg per day. The purpose of the present study was toexamine whether a high-nitrate source of drinking water isassociated with increased exposure to endogenously formed N-nitroso compounds, and to examine the association betweentotal nitrate intake and endogenous nitrosation.

Received 9/30/88; revised 2/13/89; accepted 2/21/89.The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

' To whom requests for reprints should be addressed.

MATERIALS AND METHODS

Endogenous nitrosation was investigated in a Danish rural population through measurement of urinary excretion of the nontoxic andnoncarcinogenic compound NPRO2 in 12-h urine samples following

oral intake of 500 mg L-proline. This method is a modification of theassay developed by Ohshima and Bartsch (4) which has been usedintensively to quantify the potential for endogenous nitrosation inhumans (21-22).

The Population. In the rural area of west Himmerland in northernJutland, Denmark, age- and sex-stratified samples of 18 persons wereselected from the population being served by each of 21 waterworks,i.e., altogether 378 persons. The 21 water supplies had deliberatelybeen selected to provide high variation in nitrate, concentration in thedrinking water of the participants in the study. Eight supplies had 0-5mg NOÃ¯/liter, five had 35-59 mg/liter, and eight had 60 mg/liter ormore. Thirty-nine persons were permanently or temporarily living awayfrom the "permanent" address obtained from the Danish Central Pop

ulation Register, and were considered not eligible for the study. Of 339eligible persons, 294 (87%) participated in the study. Of these, 281provided sufficient information to be included in all statistical analyses.The participation rate was uniform over the three groups of watersupplies.

Data Collection. A detailed description of the data collection procedure has been given elsewhere (20). In short, the following informationand samples were collected: (a) a questionnaire on smoking habits,history of gastric disease, and dietary habits; (hi a 24-h duplicate portionof the total diet on the day of participation from early morning to latenight. Separate containers were provided for beverages (including tapwater) and more solid dietary items; (c) a record of all dietary itemsconsumed during the 24-h period of collection of the duplicate portion;(if) a 12-h overnight urinary sample collected from l h after the eveningmeal to (and including) the first void in the following morning. Capsuleswith 500-mg L-proline were taken by the participants at the start of theperiod of urine collection. An aliquot of the urine sample was conservedwith NaOH and stored at -20"C; (e) two samples of tap water from

the residence. The data and biological samples were collected fromSeptember 1986 to March 1987.

Chemical Analyses. Nitrate in drinking water samples, duplicate dietportions, and urine samples were measured following homogenizationand extraction (20, 23). Urinary creatinine was determined by thealkaline picrate method (24).

The method used for measurement of NPRO was based on the workof Ohshima and Bartsch (4, 25). NPIC and NPRO was kindly suppliedby Dr. Bartsch, IARC, Lyon, and by the Danish Institute of ProteinChemistry, H0rsholm. Other chemicals were analytical grade.

To 15ml of thawed, centrifuged urine in a separating funnel wereadded 2 ml 20% ammonium sulfamate solution in 1.8 M sulphuric acid,4 g sodium chloride, and 247 ^g of NPIC as internal standard. Theurine was extracted three times with 25 ml dichloromethane containing10% methanol, and the organic phase was filtered though anhydroussodium sulfate into a 100 ml pear-shaped evaporation flask. The sodium sulphate was washed with extraction solvent, the combined extracts were evaporated in rotary evaporator at 35Â°Cand dissolved in 1

ml ethylacetate.A diazomethane generator was mounted in the flask and cooled in

an ice bath. Diazomethane was generated from approx. 40 mg N-methylnitrosourea by addition of 300 n\ 6 N NaOH. After methylation

2The abbreviations used are: NPRO, Â¿V-nilroso-L-proline;NPIC, iV-nitroso-L-

pipecolic acid.

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ENDOGENOUS NITROSATION IN RELATION TO NITRATE EXPOSURE

for l h the yellow extracts were transferred into 2-ml autosampler vialsclosed with teflon-lined septa. Ten M' extract was injected on a 4-mmi.d. stainless steel column packed with 10% Superox 4 on ChromosorbW with the following program: 140Â°Cisotherm for 5 min, 4Â°C/minto220"C, which was kept for 2 min. The separated nitrosocompounds

were detected with a Thermal Energy Analyser model 502 using apyrolyzer temperature at 475'C. The retention times of NPIC and

NPRO were 22.0 min and 23.7 min.Contents of NPRO was calculated from peak heights corrected for

recovery of NPIC using a standard curve with NPIC and NPROmethylated in the same way as the urine extracts. The standard curvewas linear from 0 to at least 300 ng NPRO/ml extract. The detectionlimit was better than 1.0 MgNPRO/12 h.

Statistical Analysis. First, the three groups of persons with watersupplies with low, intermediate, and high nitrate concentration in thedrinking water were compared. The Wilcoxon rank sum test was usedto evaluate differences between medians in NPRO excretion and othervariables. Secondly, the crude association of NPRO excretion withnitrate concentration in drinking water and with total nitrate intakewere evaluated, and x2 test for trend was used. The relative risk of

having NPRO excretion exceeding 1 jug/day was used as the measureof association. Thirdly, by means of multivariate maximum likelihoodlogistic regression analysis (26) using the CATMOD program in theSAS-package (27), the determinants of endogenous nitrosation measured as urinary excretion of NPRO was further evaluated. Due to theextremely skewed distribution of urinary NPRO, this variable wasanalyzed as a discrete outcome phenomenon. One ng NPRO or morein the 12-h urinary sample was considered a positive outcome, whileurinary excretion of less than 1 Mgwas considered a negative outcome.Similarly, separate regression models were evaluated to identify factorsinfluencing the risk of exceeding 5 Â¿igand 1UÂ¿Â¡gNPRO in the 12-hurine sample. The effect modification of dietary factors on the association between nitrate intake and endogenous nitrosation, was furtherevaluated among nonsmokers. Tobacco smoking was quantified as"cigarette equivalents per day": one cigar = one pipe-full = 2.5 cigarillos

= five cigarettes.

RESULTS

Table 1 shows the marked variation in the nitrate concentration of drinking water reflecting the selection of the three groupsof persons. The nitrate content of the 24-h duplicate dietportion (including beverages) and urinary nitrate varies significantly with the measured nitrate concentration in drinkingwater. Urinary creatinine is identical in the three groups. Themedian of urinary excretion of NPRO is highest in the groupwith the highest nitrate concentration in the drinking water,

but none of the pairwise differences between median NPROexcretion in the three groups are statistically significant.

Fig. 1 shows the distribution of NPRO in individual urinesamples. About half of the samples contained less than 0.5 /Â¿gNPRO while the other half contained from 0.5 to 119 /tg.Consumption of cured meat products during the 24-h periodbefore urine collection is associated with a high urinary level ofNPRO. The odds-ratio for excreting more than 1 Â¿tg/12hassociated with consumption of cured meat is 3.68 (1.27-10.67)for having more than 1 ^g NPRO/12 h, which increases to 4.63(1.54-13.87) and 9.30 (2.04-42.40) for excreting more than 5ng/12 h and more than 10 ng/12 h, respectively. This meansthat consumers of cured meat contribute markedly to the uppertail of the distribution of urinary NPRO measurements (Fig.1). It is well known that cured meat may contain up to severalgram NPRO per kilo meat product (28). Like NPRO formedin the stomach, ingested NPRO is not metabolized but is rapidlyexcreted in the urine. It is thus likely that the increased urinaryNPRO associated with consumption of cured meat representingested NPRO rather than intragastric formation.

Tables 2 and 3 show a positive association between nitrateconcentration in drinking water and nitrate intake respectivelyon the prevalence of NPRO excretion exceeding 1 ng in personswho do not smoke tobacco. NPRO excretion increases withnitrate concentration in drinking water in nonsmokers, although not statistically significant (x2 test for trend; P = 0.08)(Table 2) or in smokers and nonsmokers combined (P = 0.08).NPRO excretion increases with total nitrate intake in non-smokers (x2 test for trend; P < 0.01) (Table 3) and in smokersand nonsmokers combined (x2 test for trend; P < 0.01).

Results of the logistic regression analysis of these individualdata are shown in Table 4. From the model including sex, age,history of gastric disease, batch of NPRO analysis, urinarycreatinine concentration, and consumption of cured meat it canbe estimated that the odds-ratio for excretion of 1 ng NPRO ormore is 1.9 for an increase in nitrate intake of 50 mg/dayamong nonsmokers; this is highly significant (95% confidenceinterval = 1.39-2.58). Nitrate intake was in this model evaluated as a continuous variable with a unit = 50 mg/day. Amongsmokers of 1-20 cigarette-equivalents per day, nitrosation issignificantly increased compared with nonsmokers and nitrateintake is not a strong determinant within this group. In thegroup of heavy smokers (21+ cigarette-equivalents) nitrosationis also increased compared with nonsmokers, but the effect of

Table 1 Quantitative information from samples of drinking water, 24-h duplicate dietary samples, and overnight urinary samples in three drinking water categories

Number of samples examined given in brackets.

Drinking water category/' value of pairwise comparison of

medians

Low nitrate (L)eight water supplies (0-5 mg/li

ter)Intermediate

(I)five water sup

plies (35-59 mg/liter)High

nitrate (H)eight water supplies

(60+mg/liter)L&II&HL&HNitrate

concentration in drinking water(mg/liter)MeanÂ±standard deviation(n)Median;

quartilerangeTotalnitrate in 24-h duplicate portion(mg)Mean

Â±standard deviation(n)Median;quartilerangeNitrate

in urinary sample(mg)MeanÂ±standard deviation(n)Median;

quartilerangeUrinarycreatinine(mM)MeanÂ±standard deviation(n)Median;

quartilerangeUrinaryNPRO (>ig/l 2h)MeanÂ±standard deviation(n)Median;

quartile range0.3

Â±0.7(115)0.0;0.0-0.046.5

+43.6(114)37.2;17.5-58.336.3

+23.8(112)31.6;22.0-44.39.6

Â±4.7(115)8.2;6.3-11.62.90

Â±9.15(112)0.00;0.00-3.0546.5

Â±6.9(76)45.3;41.0-53.0102.4

Â±46.3(76)89.3;72.6-123.054.9

+26.9(71)50.3;35.8-65.69.9

Â±5.0(73)9.0;5.7-14.31.86

Â±2.85(74)0.69;0.00-2.3584.4

Â±19.2(103)80.0;69.0-96.0143.6

Â±79.8(103)122.8;87.5-187.572.6

+38.0(100)63.7;44.4-86.19.7

Â±4.8(103)9.0;6.3-11.73.75

Â±12.57(99)0.83;0.00-3.270.00010.00010.00010.460.260.00010.010.010.980.810.00010.00010.00010.340.19

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URINARY NPRO ( ug/12h)

Fig. 1. Distribution of NPRO in 285 overnight urine samples, ng/12 h. TheNPRO analysis was run in three batches with an estimated detection limit of atleast 1.00 MgNPRO/12 h. Four samples were out of the range 0-20 MgNPRO/12 h: 21, 30, 90, and 119 Mg/12 h.

nitrate appears to be reversed although the confidence intervalsare very wide.

Table 5 shows the results of further analyses of dietarydeterminants of nitrosation in nonsmokers. When informationon consumption of selected foods is added individually to thebaseline model given in Table 4, increased nitrosation is seenfor green vegetables, cabbage, and other vegetables, althoughonly the effect of green vegetables is statistically significant.Consumption of tea and vegetables on sandwiches providessignificant protection against nitrosation.

The 24-h duplicate portions were collected with use of separate containers for beverages and solid dietary items. Nitrate inthese subsamples were measured separately. It is thereforepossible to estimate the effect of nitrate in the liquids (mainlyfrom drinking water but also from fruit juices etc.) and in theof more solid dietary items [mainly from vegetables but alsofrom drinking water used in cooking (20)]. An odds ratio of1.88 (1.37-2.57) among nonsmokers for 50 mg total nitratebreaks down to 1.48 (0.95-2.32) for 50 mg nitrate in the liquidssubsample and 2.41 (1.46-3.96) for 50-mg nitrate in the sub-sample of solid dietary items, when these are considered simultaneously in the regression model.

DISCUSSION

It was the purpose of the present study to examine theassociation between nitrate intake and endogenous nitrosation

in view of the hypothesized relationship between nitrate, nitrosation, and gastric cancer. Examination of the general population exposed to various levels of nitrate is of particular importance in view of the often high and increasing exposure tonitrate from drinking water which result from intensive agricultural practices.

While no overall association is found between nitrosation inthree groups of individuals with household water-supplies with0.3, 46.5, and 84.4 mg nitrate/liter, respectively, nitrosation ofproline is strongly associated with nitrate intake in individualswho do not smoke tobacco. The nitrosation rate should theoretically depend on the square of the concentration of nitrate(29). Inclusion of the square of nitrate intake in the regressionanalysis did not improve the goodness-of-fit. Ohshima &Bartsch (4) found, in a nonsmoking individual, very low nitrosation rates at nitrate intakes below 200 mg/day and stronglyincreasing nitrosation with higher nitrate intake. Few individuals in the present study had a nitrate intake of 200 mg/day ormore, and it appears that nitrate intake increases endogenousnitrosation in nonsmokers, also at the level of 20-150 mg/daytypically found in the Danish population.

The odds-ratio of excreting more than 5 ng NPRO/12 h and10 ng NPRO/12 h for a change of 50 mg nitrate per day arenot substantially different from the 1.90 obtained with a threshold at 1 fig NPRO/12 h. The effect of nitrate intake in non-smokers is thus generally to increase the rate of endogenousnitrosation.

Endogenous nitrosation is associated with tobacco smokingand apparently independent of nitrate intake in smokers. Thi-

ocyanate is a strong catalyst of nitrosation of amines, andsmokers have three to four times higher levels of thiocyanatein saliva than nonsmokers (30). Also, thiocyanate and nitratecompete at the level of active transportation and salivary recirculation (31). Increased salivary thiocyanate levels may therefore increase the rate of endogenous nitrosation in the stomachand at the same time, for any level of nitrate intake, reduce theflow of recirculated nitrate in saliva. Our findings of an increased excretion of NPRO in smokers is in line with previousobservations (32).

Generally, vegetables are the major source of nitrate intake(15) but in Danish communities with nitrate concentration indrinking water exceeding about 50 mg/liter (20) this was notfound to be the case. Vegetables contain nitrate which mayincrease endogenous nitrosation, but vegetables also containascorbate, a strong nitrosation inhibitor (33). Our results (Table5) show that consumption of vegetables increases the endogenous formation of NPRO. The effect is strongest for greenvegetables (OR = 2.37) but the effects of cabbage (OR = 1.82),and other vegetables (OR = 1.43) is in the same direction,although these effects are not statistically significant. On theother hand, consumption of other sources of ascorbate: vege-

Table 2 Prevalence of excretion of 1 ng NPRO or more in overnight urine, in relation to nitrate concentration in drinking waterNonsmokers0Amount

NPROinNitrate

concentrationin drinkingwater(mg/liter)0-2425-4950-7475-99100+overnight

urinarysample>lMg22918107=

1Mg36142394% alMg37.939.143.952.663.6Cruderate-ratio1.001.031.161.391.68Smokers*Amount

NPROinovernighturinary

samplealMg201111113


Table 3 Prevalence of excretion of I /ig NPRO or more in overnight urine, in relation to total nitrate intakeNonsmokers"Total

nitrateintake

(mg/24h)0-49

50-99100-149150-199

200+Amount

NPRO inovernight urinary

sampleal

Mg


that nitrate in drinking water can only be one of several determinants of gastric cancer incidence in Denmark where theincidence rate of this disease has decreased steadily for severaldecades. A full understanding of the epidemiology of gastriccancer in Denmark requires, within the framework of Correa's

model, that changes in the intake of nitrate from other sourcesthan drinking water and changes in the intake of nitrosationinhibitors in this century are given consideration.

ACKNOWLEDGMENTS

The authors wish to thank the persons who participated in the study,and the following individuals for their skillful technical assistance: JetteAndersen, Niels Christensen, Charlotte Eriksen, Pia Kristiansen, Marianne Lorentzen, Maibritt Mikkelsen, Bernard Borys Szoymer, andVibe Roepstorff. The financial resources were provided by the DanishCancer Society (Krzftens Bekasmpelse) and a grant from Nordjyllandsamtskommune.

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