**Comments in Response to Publication of EPA-HQ-OW-2007-1189 FRL-8529-7
RIN 2040-AD99**

**Drinking Water Contaminant Candidate List 3 -- Draft**

**Author Joseph O. Falkinham, III**

**Department of Biological Sciences**

**Virginia Tech**

**Blacksburg, VA 24061-0406**

**Phone (540) 231-5931**

**FAX (540) 231-9307**

**E-mail <jofiii@vt.edu>**

**Note.** The recommendation reflects the views of the author and does
not represent the views of Virginia Tech.

**Recommendation**

*Mycobacterium avium* and *Mycobacterium intracellulare* (*M. avium*
Complex, MAC) should be included in the drinking water Contaminant
Candidate List 3.

**Justification for Recommendation**

(1) The prevalence and incidence of MAC disease in the United States and
    Canada is increasing.

(2) The prevalence and incidence of MAC disease is particularly
    increasing among the elderly. MAC pulmonary disease is dramatically
    increasing amongst elderly individuals (\> 60 years). In as much as
    the proportion of elderly US citizens will continue to increase, the
    increase in MAC disease will continue to increase.

(3) MAC disease has long-term adverse health, economic, and social
    effects on individuals, their families, and communities.

(4) MAC are normal inhabitants of drinking water distribution systems
    that persist, grow, and form biofilms throughout drinking water
    systems. The majority of MAC cells reside in biofilms on pipe
    surfaces and are dislodged or released by water flow to enter
    household, hospital and building water systems.

(5) Current methods for delivery of contaminant-free water actually
    select for the growth and persistence of MAC in drinking water
    distribution systems.

(6) The presence of MAC in drinking water has been linked to infection
    and disease in persons exposed to that water.

(7) Opportunities exist for reduction of health risks through imposition
    of water treatment measures.

**Details Relevant to Summary Comments**

**(1) The Prevalence and Incidence of MAC Disease is Increasing**

Recent reports document a rising prevalence and incidence of disease and
infection by *M. avium* complex bacteria (MAC) and other nontuberculous
mycobacteria (NTM). The reports have analyzed three sets of data. First
are reports of increased incidence of patients suffering from MAC or NTM
disease (Marras and Daley, 2002). Second are reports of increases in the
number of samples sent to mycobacteriology laboratories for culture and
the increased number and frequency of patient specimens yielding MAC or
NTM (Yates et al., 1997; Martin-Casabona et al., 2004; Lipsky et al.,
1984; Gordin et al., 1990; Yajko et al., 1994; Stone et al., 1997;
Wright et al., 1998; Marras et al., 2007). Third, is a report of the
increase in skin sensitivity to mycobacterial antigens over three
decades in the United States (Khan et al., 2007). All three measures
reflect the increasing burden of exposure to MAC and NTM in the United
States.

Although infections caused by nontuberculous mycobacteria, including
members of the *M. avium* complex (MAC) are not required to be reported,
estimates of disease incidence in the United States have been published.
Most estimates of infection and disease in the United States and Canada
are outdated (1960 -- 1996) and range from 0.1 to 1.8 per 100,000
(reviewed in Marras and Daley, 2002). For example, in 1987, a study
conducted by the CDC reported that the incidence of NTM disease was 1.8
per 100,000 and that for MAC alone was 1.1/100,000 for MAC (O'Brien et
al., 1987). A more recent estimate of the prevalence of pulmonary NTM
infection in Ontario (Marras et al., 2007) showed significant increases
for MAC from 5.6 (1997) to 8.4 (2003)/100,000, *M. xenopi* (another
waterborne pathogenic mycobacterium) from 2.6 (1997) to 4.2 (2003), and
rapidly growing mycobacteria from 1.2 (1997) to 2.0 (2003). Because MAC
and NTM disease is not reportable, it is likely that the estimates are
low and the prevalence of MAC and NTM disease are considerably higher.

Reports of increased frequency of MAC and NTM isolation from specimens
submitted to reference mycobacteriology laboratories have come from
England (Yates et al., 1997) and 14 European nations (Martin-Casabona et
al., 2004). A recent study of the Public Health Laboratory Information
System resulted in estimates of 3.5 and 3.7 MAC isolates (alone) per
100,000 in 1993 and 1996, respectively. If total pathogenic NTM are
included, the rates are 4.4 (1993) and 4.5 (1996). Another example of
the increasing incidence of MAC and NTM in the United States (where MAC
predominates) is evidence of the increased proportion of nontuberculous
mycobacterial isolations amongst samples submitted to laboratories in
the United States over the period 1984 to 1998. During this period of
time there was no substantial change in the incidence of *Mycobacterium
tuberculosis* infection or isolations.

Reference Specimen Number NTM (%)

Lipsky et al. (1984) 58 1 (2 %)

Gordin et al. (1990) 142 5 (4 %)

Yajko et al. (1994) 306 33 (11 %)

Stone et al. (1997) 387 96 (25 %)

Wright et al. (1998) 1315 638 (49 %)

Finally, the incidence of positive skin sensitivity reactions to
antigens prepared from *Mycobacterium intracellulare,* a member of the
*M. avium* complex, over the period 1971-1972 and 1999-2000 were
compared (Khan et al., 2007). Unlike many other bacterial pathogens,
skin sensitivity reactions to mycobacterial antigens can be used to
detect infection. The prevalence of positive *M. intracellulare* antigen
sensitivity reactions increased from 11.2 % to 16.6 % of the individuals
tested (Khan et al., 2007). Thus, individuals in the United States are
being exposed to MAC and NTM either through wider distribution (not just
southeastern), higher numbers, or more frequently.

Clearly, all three measures of MAC or NTM disease or exposure document
the increasing prevalence of MAC and NTM in humans in the United States
and elsewhere.

**(2) MAC Pulmonary Disease Incidence is Increasing Dramatically amongst
the Elderly**

The prevalence and incidence of MAC pulmonary disease amongst elderly
individuals has been increasing dramatically since it was first
described (Albelda et al., 1985; Prince et al., 1989). This new
presentation of MAC pulmonary disease appears in elderly men and women
who lack any of the classic risk factors for mycobacterial pulmonary
disease (Prince et al., 1989). The only common feature is that the
infected individuals are elderly and low weight.

Increases of MAC disease amongst the elderly, geriatric population have
been noted in several published community-based studies, not at referral
hospitals. In particular, increases have been documented in two
geographically separated regions of the United States, Portland, Oregon
(Reich and Johnson, 1991) and Chapel Hill, North Carolina (Kennedy and
Weber, 1994). Similarly, increases amongst the elderly have been noted
in Calgary, Alberta, Canada (Field et al., 2004) and Toronto, Ontario,
Canada (Marras et al., 2007). Thus, the dramatic increase in MAC
pulmonary disease is not restricted geographically, but occurs across
the United States and Canada. One common feature of persons living in
those areas in the united States and Canada is access to high quality
treated drinking water; a normal habitat of MAC and NTM.

In as much as all models of future U.S. population composition project
that the proportion of elderly will increase, it is logical to expect
that the incidence and prevalence of MAC and NTM pulmonary disease will
continue to increase. In fact, the increases will accelerate as the
proportion of elderly amongst the US population increases.

Other groups of individuals, whose incidence in the US population is
expected to increase include patients that arte immunosuppressed as a
consequence of transplantation or chemotherapy. Members share the common
characteristic of reduced immune competence and greater susceptibility
to infection. Both transplant (Simpson et al., 1982) and
immunosuppressed patients (Skogberg et al., 1995) as well as those with
malignancies (Claass et al., 1995) are more susceptible to MAC and NTM
infection. Again, as is the case for the elderly, it is expected that
the proportion of those individuals is expected to rise in the United
States.

**(3) MAC Disease has Strong Adverse Health, Economic, and Social
Effects on Individuals**

MAC and NTM pulmonary disease has severe adverse effects on persons with
the disease. The list of salient clinical symptoms of MAC and NTM
disease includes:

Cough

Malaise and Fatigue

Fevers and Night Sweats

Anorexia and Weight Loss (Prince et al., 1989; Field et al., 2004)

Thus, there can be no doubt that MAC and NTM disease dramatically reduce
the quality of life for infected persons.

Recommended MAC and NTM therapy involves multi-drug regimens (Field et
al., 2004; Griffith et al., 2007). Guidelines from the American Thoracic
Society and Infectious Disease Society of America recommend combinations
of two, three, and four antibiotics (Griffith et al., 2007). It is
well-established that treatment with each drug is accompanied with
side-effects. Further, rather than simply adding side-effects, there are
drug interactions that multiply the side-effects. In treatment of MAC
and NTM disease, high failure rates of treatment are due to an inability
to tolerate side-effects (Field et al., 2004).

Long treatment durations are characteristic of treatment of MAC and NTM
infections (Griffith et al., 2007). Relapses are common amongst MAC and
NTM pulmonary patients, requiring hospitalization and additional medical
attention. Both lead to severe economic hardships on MAC- or
NTM-infected individuals that are beyond those caused by the symptoms
that reduce energy levels and mobility. Multi-drug regimens are quite
expensive, particularly because mycobacteria are not susceptible to
antibiotics used to treat other bacteria infections.

**(4) MAC are Normal Inhabitants of Drinking Water Distribution
Systems**

Members of the *M. avium* complex (MAC) as well as other nontuberculous
mycobacteria (NTM) are normal inhabitants of the human environment. In
addition to natural waters (Falkinham, et al., 1980) and soils (Brooks
et al., 1984), MAC and other NTM are also normal inhabitants of drinking
water distribution systems (Aronson et al., 1999; Covert et al., 1999;
Falkinham et al., 2001). As the water distribution systems were located
throughout the United States and employed different methods of water
treatment and had different organic matter contents, it is likely that
most, if not all, US drinking water systems carry a resident and
persistent population of MAC and NTM.

MAC and other NTM are not contaminants of drinking water distribution
systems, but they grow in the distribution system. In fact, the further
the distance the water sample is collected in a distribution system, the
higher the numbers of MAC (Falkinham et al., 2001).

In addition to water distribution systems MAC and NTM have been shown to
increase in number in hospital hot water systems (du Moulin et al.,
1988; Kusnetsov et al. 2003). What is troubling about this discovery is
that hospitals are comprised primarily of persons more susceptible to
infection as a consequence of their conditions leading to
hospitalization. Further, the information on hospitals suggests that MAC
and NTM, whose original source is the public or private water supply,
can populate the water systems of buildings and homes.

**(5) Drinking Water Treatment and Practice Selects for MAC Growth and
Persistence in Drinking Water Systems**

MAC are at least 100-times more resistant to chlorine, chloramine,
chlorine dioxide and ozone than *Escherichia coli*, the standard for
disinfection (Taylor et al., 2000). Consequently use of any disinfectant
leads to killing of other microorganisms and the survival of MAC and
other NTM. The hydrophobic cell envelope of MAC and other NTM leads to
their preferential attachment to surfaces where they grow and form a
biofilm. Thus, MAC and NTM are not washed out of a drinking water
distribution system. Further, biofilm-grown MAC are significantly more
resistant to disinfectants than are those grown and exposed in
suspension (Steed and Falkinham, 2006). MAC can grow in drinking waters
at assimilable organic carbon (AOC) concentrations as low as 50 µg/L;
they are oligotrophic (Norton et al., 2004).

The goal of water treatment is to reduce the number of pathogenic
microorganisms and organic and inorganic chemicals in water. However,
achieving those aims using chemical disinfection selects for MAC and
NTM. Addition of disinfectant and reduction of AOC both select for MAC
and NTM persistence and growth. In the absence of competitors,
disinfectant-resistant, slowly growing MAC and NTM on the surfaces of
pipes can utilize all the available nutrients for growth. As the
mycobacteria grow cells are released into the water where they can
colonize and grow in new habitats; for example hospitals, buildings, and
households.

A recent, troubling report indicates that disinfectant changes, to
reduce the formation of trihalomethanes (Stage 1 Disinfection-Byproducts
Rule, January 1, 2002) may lead to increases in MAC and NTM in drinking
water distribution systems. A change from chlorine to chloramine in the
drinking water system of Pinellas County, Florida led to an increase in
the frequency of isolation and number of MAC and NTM (Pryor et al.,
2004). Thus, changes in water treatment to reduce chemical exposures,
may select for increased MAC and NTM numbers.

**(6) The Presence of MAC in Drinking Water has been Linked to Disease
in Persons Exposed to that Water.**

MAC in drinking water has been epidemiologically linked to disease in
humans. Patients in a Boston AIDS outpatient clinic were infected with
*M. avium* that shared the same DNA fingerprint pattern as M. avium
isolates recovered from the water used to prepare coffee (von Reyn et
al., 1994). More recently, the fingerprints of *M. avium* isolates
recovered from the hot and cold water and biofilm in a bathroom
showerhead in a condominium in New York were shown to be clonally
related to the *M. avium* isolate recovered from a resident who used the
shower regularly (Falkinham et al., 2008). The significance of the
latter case lies in the fact that the resident was young, not
immunodeficient, and had none of the classic risk factors for *M. avium*
(Falkinham et al., 2008).

(**7) Opportunities Exist for Reduction of Health Risks Through
Imposition of Water Treatment Measures.**

Although MAC and NTM are disinfection-resistant, they are as susceptible
to ultraviolet light (UV) as are other microorganisms, such as
*Escherichia coli*. Thus, UV-disinfection is a viable and alternative
means for reducing numbers of MAC and NTM in drinking water.

Numbers of MAC in drinking water systems are correlated with particulate
matter (Falkinham et al., 2001). MAC and NTM are bound to particulates
because of their very high cell surface hydrophobicity (Stormer and
Falkinham, 1989; Bendinger et al., 1993). If particulate matter is
effectively removed from water entering and leaving treatment
facilities, MAC and NTM numbers will be reduced.

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