Trimethylamine

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented publication which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Urinary excretion of methylamines in men with varying intake of fish from the Baltic Sea

Author:

Svensson, B.

Year:

1994

Bibliographic source:

J. Toxicological Environ. Health 41(4): 411-420.

Materials and methods

Type of study / information:

The authors report data on the excretion of DMA, TMA, and TMAO in urine of humans, which display good correlations with oral intake of tertiary aliphatic amines and their precursors. Analysis of these amines in urine from subjects with different fish consumption therefore offers the possibility of studying dietary exposure to these potentially harmful substances.

Endpoint addressed:

basic toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Levels of dimethylamine (DMA), trimethylamine (TMA) and trimethylamine N-oxide (TMAO) in urine were measured in 44 men with different fish consumption habits.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Trimethylamine

EC Number:

200-875-0

EC Name:

Trimethylamine

Cas Number:

75-50-3

Molecular formula:

C3H9N

IUPAC Name:

N,N-dimethylmethanamine

Method

Ethical approval:

not specified

Results and discussion

Results:

 The levels of TMA and TMAO in urine were significantly associated with the weekly intake of fish and also the moment of sampling after consumption, while no such relation was found  for DMA.

Any other information on results incl. tables

The present subjects excreted 24 mmol/mol creatinine (median; range 5—46) of DMA, 0.43 mmol/mol creatinine (median; range 0-2.7) of TMA, and 38 mmol/mol creatinine (median; range 8-290) of TMAO. The ratio of excreted TMAO to TMA + TMAO x 100 (TMAO%) was 97-100.

The high consumers group had a higher urinary level of TMA than the nonconsumers (Table 1). For DMA and TMAO, there were no statistically significant differences. There were no differences between the groups in ratio between excreted TMAO and TMA + TMAO CTMAO%).

TABLE 1.Age, Consumption of Fish and Milk Fat, Serum Levels of n-3 Polyunsaturated Fatty Acids (n-3 PUFAs), and Urinary Levels of Dimethylamine (U-DMA), Trimethylamine (U-TMA), and Trimethylamine N-Oxide (U-TMAO) in Three Croups of Men with Different Fish Consumption (Medians and Ranges)
	Fish consumption
Parameter	No (n=10)	Moderate (n = 13)	High (n = 21)
Age (yr)	40 (25-56)	42 (26-50)	44 (30-53)
Total fish intake (g/wk)	0	390 (220-650)	1150^a (700-1850)
n-3 PUFAs in serum (wt%)	5.8 (4.3-7.9)	7.4^b (5.3-9.7)	10.6^a (7.2-19.0)
U-DMA (mmol/mol creatinine)	27 (17-31)	25 (16-35)	23 (4.6-46)
U-TMA (mmol/mol creatinine)	0.20 (0.2-0.3)	0.23 (0.1-1.0)	0.32^c(0-2.7)
U-TMAO (mmol/mol creatinine)	38 (30-1 20)	34 (20-92)	47 (8.5-290)
U-TMAO%	99 (99-100)	99 (98-100)	99 (97-100)
Note. U-TMAO% indicates quotient between U-TMAO and sum of U-TMA + U-TMAO, x 100.
^aSignificant at p = .0001 as compared to moderate consumers.
^bSignificant at p = .0001 as compared to nonconsumers.
^cSignificant at p = .05 as compared to nonconsumers.

The urinary levels of TMA (Fig. 2; r = 47, p = .001) and TMAO (Fig. 3; r = .53, p = .0002) correlated significantly with weekly fish intake. For DMA, no corresponding correlation was found. Also, there was an association between serum levels of n-3 PUFAs and urinary levels of TMA and TMAO (Fig. 4). The n-3 PUFAs did not correlate with DMA.

The TMA, TMAO, and DMA levels were similar in the three consumption groups, when only subjects without any fish consumption in the day before sampling were regarded (Fig. 5). Among the moderate consumers, only three subjects reported fish consumption during the day before sampling; they did not differ from the other five moderate consumers in urinary levels. In the high consumers group, however, 11 subjects, who had consumed fish close to sampling, had numerically higher levels of TMA and TMAO than the 8 ones without any recent consumption, but the differences were not statistically significant (p = .07 and .10, respectively).

DISCUSSION

To our knowledge, data on excretion of DMA, TMA, or TMAO in populations, related to their fish consumption, have not been previously reported.

Levels of TMA and TMAO increased with increasing fish consumption, indicating an exposure of these substances from dietary fish. The association with fish consumption is supported by the correlation between urinary amine levels and serum levels of n-3 polyunsaturated fatty acids, which can be used as markers offish intake (Svensson et al., 1993). Fish intake explained about one-fourth of the variance in excretion of TMA and TMAO. However, there was no impact on urinary DMA concentrations by fish consumption. The levels of the latter amine were in accordance with earlier reports (Zeisel eta!., 1988; Lundh and Akesson, 1993).

Among high consumers of fish, those who had eaten fish close to urine sampling had TMA levels almost four times higher than those without such a recent intake. This is explained by the fact that the methylamines under study have short (about 2 h) half-lives in humans (Al-Waiz et al., 1987b). Urinary levels of these amines thus mainly reflect recent intake, and are not suitable markers of long-term exposure. Among the moderate consumers, there were no corresponding dependence on recent intake. This may be due to a wide range of amine intake, due to variations in the levels of amines in the fish eaten, which is lower in fresh water than in brackish water, which, in turn, is lower than in marine fish (Singer and Lijinsky, 1976; Spinelli and Koury, 1981; Perez Martin et al., 1987; Rehbein, 1988; Ayesh and Smith, 1990). The moderate consumers group consumed all three types, while the high consumers group almost exclusively had brackish water fish. Moreover, they had a mixture of fresh and frozen fish; the former has lower methylamine levels than the latter (Rehbein, 1988; Careche and Tejada, 1990). Also, it should be noted that the number of subjects in all groups is small.

The urinary amine levels found were low in comparison with other studies on methylamine excretion after challenge through fish consumption (Zeisel

and DaCosta, 1986). This was probably not due to analytical differences. However, it may be explained by the fact that the high fish consumers under study had fish from the Baltic Sea, which has brackish water and thus produces fish with rather low levels of methylamines. Also, fresh fish dominated the diet of these subjects.

None of the subjects under study displayed a low capacity to metabolize methylamines (all had high TMAO%), a phenomenon associated with fish odor syndrome, which is a rare metabolic error.

DMA was present in urine samples from all subjects. However, there is no information on what levels are associated with adverse effects. The concentrations were not significantly higher among the fish consumers. Thus, there is no reason to believe that there was any significant fish-associated formation of NMDA in this population. Hence, no analyses of NMDA were performed. However, the risk might be different in persons who are extreme consumers of fish from marine waters and/or of fish that has been stored deep frozen for a long time.

Applicant's summary and conclusion

Executive summary:

Fish contain methylamines, especially trimethylamine N-ox/de (TMAO), trimethylamine (TMA), and dimethylamine (DMA). Further, DMA may he formed from TMA and TMAO. DMA is a precursor of nitrosodimethylamine (NDMA), which is a potent carcinogen. Levels of DMA, TMA, and TMAO in urine were used as indicators of the dietary exposure and in vivo formation of these amines in 44 men, representing 3 groups with different fish consumption habits. The levels of TMA (median 0.24 mmol/mol creatinine; range 0-2.7) and TMAO (median 38 mmol/mol creatinine; range 8-290) were significantly associated with the weekly intake of fish (r = .47, p - .001, and r = .53, p = .0002, respectively), while no such relation was found for DMA (median 24 mmol/mol creatinine; range 5—46). Further, urinary levels of TMA and TMAO were dependent on recent intake of fish.