Silica and renal diseases: no longer a problem in the 21st century?

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Many women have reported urinary problems . . . Maybe

this article has some answers as to why.

Rogene

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JNEPHROL 2001; 14: 228-247

Silica and renal diseases: no longer a problem in the

21st century?

Piero Stratta1, Caterina Canavese1, Alessandra

Messuerotti1, Ivana Fenoglio2 and Bice Fubini2 -

Departments of Internal Medicine, Nephrology Section1

of the Faculty of Medicine, S.Giovanni Molinette

Hospital, Chemistry IFM2 of the Faculty of Pharmacy of

the University of Turin, Turin - Italy

ABSTRACT: Silicosis and other occupational diseases

are still important even in the most developed

countries. In fact, at present, silica exposure may be

a risk factor for human health not only for workers

but also for consumers. Furthermore, this exposure is

associated with many other different disorders besides

pulmonary silicosis, such as progressive systemic

sclerosis, systemic lupus erythematosus, rheumatoid

arthritis, dermatomyositis, glomerulonephritis and

vasculitis. The relationships between these

silica-related diseases need to be clarified, but

pathogenic responses to silica are likely to be

mediated by interaction of silica particles with the

immune system, mainly by activation of macrophages. As

regards renal pathology, there is no single specific

clinical or laboratory finding of silica-induced

nephropathy: renal involvement may occur as a toxic

effect or in a context of autoimmune disease, and

silica damage may act as an additive factor on an

existing, well-established renal disease. An

occupational history must be obtained for all renal

patients, checking particularly for exposure to

silica, heavy metals, and solvents.

Key words: End stage renal disease, Nephropathy,

Occupational dust diseases, Occupational exposure,

silica

Background

Why should we pay attention to silica in this century?

Some nephrologists believe it is an outdated problem,

and " silica " and " silicosis " are just words evoking

dusty environments and the coal mines of yore, before

the industrial revolution. Theoretical knowledge and

technical improvements have dramatically reduced many

occupational diseases, but Silicosis and other related

diseases are still a problem even in the most

developed countries (1-6).

The aim of this review is to provide sufficient

evidence to convince readers that silica exposure is

still a risk factor for human (including renal)

diseases and - even more important - is only one

aspect of the multifactorial damage caused by

occupational and environmental pollution to human

health .

To motivate readers, we would like to challenge them

by asking a few questions:

1. Can you list one autoimmune disease eligible for

compensation as occupational-related disorders in

miners?

2. Could you list a) at least five modern occupational

risks for silica, besides in mines, and at least

three potential ways by which silica can enter the

body of people as consumers, apart from job-related

risk?

3. Can you guess how big the gap is between the

estimated association for toxic occupational exposure

and end-stage renal diseases in epidemiologic survey

from nephrology or occupational health centers?

The answers are:

1. Systemic progressive sclerosis.

2. As examples a) Dental technician, abrasive scouring

powder producer, janitor or cleaner, truck driver,

Inhalation of scouring powder, silica-based cosmetic

skin-creams, oral drugs or other products containing

silica as additive.

3. Discrepancies have been as high as 5% from

nephrology to 50% from occupational health centers in

a same year.

Introduction

Exposure to several metals can cause nephrotoxic

syndromes. Gold, bismuth and mercury have been

incriminated as responsible for immune-mediated renal

damage eventually leading to nephritic syndrome. Heavy

metals such as cadmium, lead, mercury, copper and

uranium have been associated with interstitial

nephritis and functional proximal tubular

abnormalities mimicking the Fanconi syndrome. Bismuth,

arsenic, cadmium, gold, mercury, copper and uranium in

large doses can lead to acute tubular necrosis. For

silica, evidence points to a causal relationship with

two types of renal damage: toxic and immune-mediated.

The authors of this review are convinced that the

silica hazard must still be recognized as a persisting

problem for humans in the 21st century.

From the days of early deaths of Carpatian miners in

the middle of the 16th century, leading to the common

observation of women with seven husbands " ... all of

whom this terrible consumption [due to the corrosive

qualities of the dust] has carried away " (7), a subtle

but firm link runs through the centuries up to the

case reported in 1979 (8) of a woman with widespread

silicotic noduli, glomerulosclerosis and systemic

vasculitis 25 years after intentional inhalation of

abrasive scouring powder. She enjoyed the smell of

this particular cleanser (Ajax) and would cut the

container in half and take deep breaths from each

opened portion for some months when she was ten-years

old. There are also cases of Goodpasture syndrome

after silica exposure (9) or women with scleroderma

after using cosmetic day-cream containing collagen and

silicon-based products (10).

This review will look at other underestimated causes

of silica exposure not only for workers but also for

consumers, and at the possible reasons for links

between silica and some human (including renal)

diseases. We will analyze the main papers dealing with

this topic, from anecdotal reports to evidence-based

worldwide epidemiological studies done in nephrology

and occupational health centers.

What is silica?

Chemical structure

Let us start by explaining what the common word

" silica " means, as there are several similar names

that mean completely different things (Tab. I).

Silica is a general name that covers a variety of

substances containing two major elements: silicon and

oxygen. These are combined in the stoichiometric ratio

of 1:2, so that the commonly used formula for silica

is SiO2.

Unlike other compounds such as water (H2O) or carbon

dioxide (CO2), silica does not exist as a discrete

molecule, but consists of a series of silicon (Tab. I)

and oxygen atoms bonded together to form a large

macromolecular structure in which the fundamental unit

is the silicon centered tetrahedron SiO44- (Fig. 1,

see WEB edition). The units are linked through the

oxygen atoms which are shared between two neighboring

tetrahedra. They can be linked in different ways to

form a variety of polymeric structures. These silica

polymorphs have three-dimensional structures in which

the arrangement of the tetrahedra differ one from the

other.

Silica occurs naturally in crystalline or in amorphous

forms. In the crystalline forms, the tetrahedra are

lined up in order and create a repeatable pattern;

conversely, in the amorphous forms, the bonds are

randomly oriented and the structure lacks periodicity

(Fig. 1, WEB).

Table II lists the most common forms of silica,

classified as amorphous and crystalline, synthetic and

natural. The term biogenic refers to silica

originating in living matter, including bacteria,

fungi, sponges, plants and diatoms.

Quartz constitutes the overwhelming majority of

naturally existing crystalline silica (12% of the

earth's crust by volume, Fig. 2a, WEB), so that the

term quartz is often misused to refer to crystalline

silica. Quartz is a constituent of rocks (granite,

sandstone, etc) and makes up 90-95% of sand. Other

less common crystalline silica polymorphs are

cristobalite and tridymite (1), coesite and

stishovite.

The amorphous natural forms can be either of mineral

origin, such as hydrous silica (for example opal, Fig.

2b, WEB), vitreous silica, or of biogenic origin. The

two main biogenic silicas are diatomaceous earth,

formed by the deposition in the earth of the siliceous

frustules of diatoms (which extract silica dissolved

in water to form their structures or shells), and

silica from crop plants, which accumulate silica in

their tissues to promote structural integrity and to

protect against plant pathogens and insects) such as

sugar cane, rice, canary grass and millet.

Diatomaceous earth contains small amounts of

crystalline silica, mainly cristobalite, which

significantly increases on heating (calcination), to

remove impurities (11).

Synthetic silica is generally produced in the

amorphous forms, examples being pyrogenic, fumed and

precipitated silica.

Synthetic crystalline silica are not very common, but

examples are some high silica forms (porosils) similar

to the most common aluminosilicates called zeolites

(12).

Widely found compounds of silicon are silicates (Tab.

I), in which the SiO44- tetrahedra are linked in

chains, double-chains or sheets. Examples of silicates

are mica, clays and amphibole (including most

asbestos). Silicates and aluminosilicates are by far

the most widespread rock-forming minerals (Fig. 3,

WEB).

Silicon may also be dissolved in water or in

biological fluids as silicic acid Si(OH)4. Silicic

acid is the most bioavailable form of silicon, and

accounts for 20% of the total silicon ingested by

humans, normally in water and drinks. It is readily

absorbed and rapidly excreted in urine and seems to be

involved in the homeostasis of aluminum, iron and

copper.

A different class of compounds containing silicon are

the silicones (Tab. I). Silicones are synthetic

polymers with a linear, repeating silicon-oxygen

backbone (-Si-O-Si-) in which organic groups, such as

methyl and phenyl groups, are bonded to the silicon

atoms. Depending on what kind of organic residue is

bonded to the silicon atoms, a wide variety of

products are synthesized, with different

consistencies, from oil to elastomers. Silicones are

used as lubricants, seals, waterproofing agents,

cosmetics, and biomedical implants.

FIG 1

TABLE I - NOMENCLATURE AND CHEMICAL STRUCTURE OF

SILICON-RELATED COMPOUNDS

TABLE II - THE MOST COMMON FORMS OF SILICA AND THEIR

ORIGINS

Use and Production

Silica's pervasiveness in our technology is matched

only by its abundance in nature. It is found in

samples from every geological era and from every

location around the globe. Silica has shaped human

history since the beginning of civilization. From the

sand used for making glass ­ its oldest and main use

throughout history ­ to the piezoelectric quartz

crystals used in advanced communication systems,

crystalline silica has been a part of our

technological development (1).

Silica, both crystalline and amorphous, has a wide

spectrum of industrial applications. The main uses and

production areas of crystalline and amorphous silicas

are shown in Table III (1). Most silica in commercial

use is obtained by processing (crushing, milling,

heating, calcining) from naturally occurring sources,

but several synthetic amorphous silicas are prepared

too, and quartz monocrystals can be cultured.

Finely ground crystalline silica (Fig. 4, WEB) is also

known as silica-flour, used industrially as an

abrasive cleaner and as an inert filler. Silica flour

is found in toothpaste, scouring powder, and metal

polish. It is an extender in paint, a wood filler, and

a component in road surfacing mixtures. It is also

used in some foundry processes.

The original micromorphology of diatomites (Fig. 5,

WEB), characterized by a wide range of porous and fine

structures and shapes, is partially retained after

calcination, which considerably increases the amount

of crystalline material in the originally amorphous

silica. This intricate microstructure explains why its

main use is to filter or clarify dry cleaning

solvents, pharmaceuticals, beer, wine, municipal and

industrial water, fruits and vegetables, oils and

other chemical preparations. The next most important

use is as filler in paint, paper and scouring powder,

as it imparts abrasiveness to polishes, flow and

colour to paints, reinforcement to paper.

Synthetic amorphous silica has many uses, mainly in

reinforcement of elastomers and thickening of various

liquid systems. In the laboratory and in industry, it

is widely used as stationary phase for chromatography

columns. Vitreous silica products are used for

filtering material of precise measurements for

environmental pollution, and for heat insulation.

Polished vitreous silica plate for optical science has

excellent ultraviolet-visible-infrared transparency

and heat resistance. Therefore, it is used for lenses,

prisms, laser parts, optical fibers, spectrography

cells, window plate for high-temperature work, lens

windows for laser nuclear fusion, and for various

kinds of laser.

TABLE III - USE AND PRODUCTION OF CRYSTALLINE AND

AMORPHOUS SILICA COMPOUNDS

Silica compounds Use Production

Crystalline Glass-making Country Tonnes/year

sand Foundry 106 tonnes

and Metallurgical Europe 48.1

gravel Abrasive USA 27.9

Fillers (rubber, paints, putty, whole-grain) Asia 8.2

Construction Oceania 3.3

Ceramic (pottery, brick, tile) South America 3.1

Filtration (water, swimming pools) Africa 2.6

Petroleum industry

Recreational (golf, baseball, volleyball, play sand,

beach, traction-engine, roofing granules and filler)

Brazil

quartz crystals Electronics industry Angola

Optical component industry India

Jewellery Madagascar

Amorphous:

natural

(diatomaceous earth) Filtering agent USA 671

r for pesticides Europe 611

Filler in paints and paper, rubber goods, Asia 79

Laboratory absorbent and anti-caking agent South

America 56

Refractory products Oceania 11

Abrasives Africa 6

synthetic Rubber reinforcing 103 tonnes

Toothpaste: cleaning, rheological control

Paints: flatting worldwide 1100

Resins: thickening

Foods, creams: free-flow, anti-caking additives

Pharmaceutical preparations: excipient

Desiccant, absorbent

Exposure

It is important to clear one's mind of the common bias

that potential exposure only means the presence of an

excess of crystalline silica particles in the air and

is only for specific categories, namely blue-collar

workers. This review deals not only with the risk of

the most severe health effect ­ " silicosis " ­ but also

with the ways by which silica can come into contact

with human cells.

Occupational respiratory exposure to crystalline

silica dust has long been recognized as the main

culprit, the amorphous form being considered of low

toxicity. However, some key notions must be kept in

mind:

1) Amorphous silica may contain crypto-crystalline

silica or may be converted into crystalline forms

during processing; for instance, in commercial

products, a large proportion of the amorphous silica

in diatomaceous earth is converted into cristobalite.

Thermal treatment of amorphous silica dust may change

it into micrometer-sized silica crystals. As an

example, amorphous diatomite earths, if converted to a

crystalline form, turn out to be one of the most

fibrogenic forms of silica (3);

2) The most dangerous silica powders are those whose

particles have a mean diameter less than 5µ, the

so-called respirable fraction. Airborne silica

particles are not visible but may be very dangerous.

Particles with a diameter larger than 5µ hardly reach

the distal part of the respiratory tract because they

are intercepted and removed by the mucociliary

escalator.

3) Data on non-occupational exposure to silica are

scant. There is evidence, however, that exposure to

both crystalline and amorphous silica may occur during

not only the production but also the use of natural

and synthetic compounds. There are reports of silica

exposure in people of any social and economic class

(10).

4) Beside inhalation, there are other ways by which

silica can enter the human body. As an example,

amorphous silica may be absorbed by skin or ingested

as a minor constituent (<2%) of foods and drugs.

The main activities in which workers are exposed to

silica are shown in Table IV. The risk is acknowledged

in surface and underground mining, tunneling and

quarrying but, although substantial, it is often

unrecognized in the construction industry and other

manufacturing sectors. Besides these activities,

mainly involving exposure to crystalline silica, other

occupations, cause exposure to amorphous silica. These

include manual or mechanical harvesting of sugar cane,

rice, grain (biogenic silica fibers), production and

processing of diatomaceous earths, manufacture of

synthetic silica, ferrosilicon industries (silica

fume).

Recent evidence does not support the view that

silicosis is only a disease of historical interest.

First, despite continuous improvement in safety

measures and controls in occupational settings in

which a silica-hazard is well recognized

(approximately 3 million workers in USA and Europe are

exposed to crystalline silica) (13), the US

Occupational Safety and Health Administration (OSHA)

reported, as recently as six years ago, that in 48% of

255 industries average overall exposure exceeded

permissible exposure levels (<0.09 mg/m3) (Fig. 6,

WEB).

Second, even in occupations not usually regarded as

hazardous, such as denture manufacturing, 18% of 66

personal exposures to crystalline silica measured in

32 workshops in France were above the occupational

exposure limits (14).

Third, occupational exposure has been demonstrated in

previously underestimated industries/occupations, such

as electrical and electronic machinery, textiles

(cotton, wool), rail transport, crane and tower

operators, truck drivers, supervisors, precision

production workers, proprietors, managers and

administrators, operating engineers, janitors or

cleaners, rock or glass sculptors, foundry or

sand-related industrial engineers and chemists, dental

prosthesis makers, toothpaste manufactury or scouring

powder manufacturing workers and engineers (15-17).

Lastly, non-occupational exposure has also to be

considered.

Environmental exposure: it has been estimated that

respirable crystalline silica levels are in the range

of 1-10 mg/m3, i.e 10-100 times below the permissable

occupational exposure level) in urban and rural

settings, but no data are available for ambient levels

of amorphous silica. However, exposure may be higher

during the use of consumer or hobby product, such as

cleaners, cosmetics, art clays and glazes, talcum

powder, paint, or pet litter.

Silica in water: silica may be present in water as

quartz particles and diatom fragments.

Silica in foods: amorphous silica is incorporated in a

variety of food products as anti-caking agent at

levels up to 2% by weight (beverage mixes, salad

dressings, sauces, gravy mixes, seasoning mixes,

soups, spices, snack foods, sugar substitutes,

desserts). Other uses are for clarification, viscosity

control, anti-foaming, anti-caking and as an excipient

in the pharmaceutical industry for drugs and vitamin

preparations.

Advice from OSHA concludes that as silica is so

abundant in our natural resources it is quite possible

that we encounter it without knowing it.

To call the attention of nephrologists to these

uncommon ways of encountering silica as a risk for

renal disease, we shall just make two points briefly

here that will be explained better further on:

1) some authors suggest that Balkan nephropathy may be

associated with consumption of water rich in silica;

2) in the Negev Desert in Israel, the Bedouins, a

population likely to have maximal exposure to dust

storms ­ which are likely to increase respiratory

uptake of silica ­ have higher rates of ESRF than do

Jews in the age group over 60 years (18).

Furthermore, some concern has been expressed on a

possible association between silica in food and

esophageal cancer (19).

TABLE IV - EXPOSURE TO CRYSTALLINE AND AMORPHOUS

SILICA

When silica and cells meet

Silica and human diseases

The relationship between exposure to crystalline

silica and lung disease has been known since ancient

times. Among the Greeks and Romans, Hippocrates

described a metal digger who breathed with difficulty

and Pliny mentioned protective devices to avoid

inhalation of dust (3, 20). The disease was classified

as pneumoconiosis (from the Greek word *o***= dust),

generally " dust in the lung " , while the specific term

silicosis was originally proposed at the end of the

19th century (3, 21).

Chronic and acute silicosis are the best known

diseases associated with silica inhalation, and the

correlation with lung cancer is still controversial

(22).

However, it is now clear that silica exposure is

associated with many other different disorders besides

pulmonary silicosis and acute silico-protein

emphysema, such as progressive systemic sclerosis,

systemic lupus erythematosus (SLE), rheumatoid

arthritis, dermatomyositis, glomerulonephritis (GN)

and vasculitis (8-10, 16, 23-26).

The relationships between the different silica-related

diseases need to be clarified but the different

pathogenic responses to silica may well be mediated

partially by common mechanisms, in particular as

regards the interaction of silica particles with the

immune system.

Although still only partially clarified, the accepted

mechanisms for silica pathogenicity involve the

activation of alveolar macrophages (Fig. 7). Once in

contact with macrophages, the particle can be

phagocytosed and may follow two different pathways: if

the engulfed particle does not interfere with normal

Ca2+ cell exchanges or damage the phagolysosomal

membrane it is cleared from the lung through the

" successful " path in Figure 7. If, on the other hand,

the particle activates the macrophages and eventually

causes their death ( " unsuccessful " path in Fig. 7),

the cell leaves a free particle in the lung and

releases cytokines and oxidants (ROS, RNS) into the

medium, which can reach target cells. A continuous

ingestion-reingestion cycle with cell activation and

death is thus established.

The prolonged recruitment of macrophages and

polymorphonuclear (PMN) cells causes inflammation,

regarded as the primary step in silica-related

diseases. The particles engulfed by PMN or protein

adsorbed on particles like myeloperoxidase can cause

an autoimmune response (Fig. 7, bottom).

Not any silica particle can activate this mechanism

all on its own. The toxicity is related only to

certain solid forms of silica. The soluble form of

silica, silicic acid, is an ubiquitous, definitely

non-toxic compound. Thus silica should be regarded as

a particulate, not a molecular, toxin. The differences

between these two categories are important (27). The

relationships between silica exposure and human

diseases when dealing with toxic effects must be

considered not only in terms of a quantitative massive

dose/effect ratio, but also considering the size and

reactivity of the surface of the silica particles.

A large variety of compounds differing in

crystallinity and origin are found under the same

chemical formula, SiO2. The word " quartz " , usually

brings to mind the transparent, elegant big crystals

on show in shops and museums or discovered in the

cleft of a mountain rock (Fig. 2a, WEB), but in the

laboratory quartz is a powder with particles <5

microns in diameter (Fig. 4, WEB).

Dusts made from the different silica forms can differ

in particle size, crystal faces exposed,

micromorphology, levels of contaminants, and chemical

functions at the surface. Beside their aerodynamic

properties (shape and size) which are influential for

particles reaching the distal part of the respiratory

system (28), the different biological responses

elicited by silica dusts strongly depend on the

surface state of the particles (3, 29, 30).

No single surface property responsible for disease has

yet been found: polarity, crystallinity and

contaminants are all relevant to the the biological

response to quartz dust. Typically problematic dust is

crystalline, with tetrahedrally coordinated silicon

atoms, hydrophilic, not contaminated by aluminium or

other elements. However, many properties are involved

in the final response of human cells to silica,

including micromorphology, surface area,

hydrophilicity of the surface, surface contaminants

and defects, adsorption of endogenous molecules, free

radical release, reactivity with endogenous molecules.

Fig. 7 - Mechanisms for silica pathogenicity through

activation of alveolar macrophages.

Micromorphology

The micromorphology of the silica particulates to

which people are exposed depends on the crystallinity

and on how the silica particulates were formed. Ground

samples have very sharp edges and vary widely in

particle size, as shown in Figure 4 WEB, where smaller

particles are held on the surface of bigger ones by

surface charges (30). Particles from diatomaceous

earth have an almost infinite variety of shapes,

originating in the living material from which they

came (Fig. 5, WEB). Generally, the synthetic forms of

silica have very regular particles, either spherical

in as pyrogenic silicas, or polyhedral as in porosils,

hydrotermal quartz, etc.

In both types of particles, surface irregularities

play a role in the pathogenic response. The rod-like

shape of crystallites enhances the cytotoxicity of

silica toward macrophages (12, 31). Unlike inert

amorphous silicas, pathogenic silicas have steps and

sharp edges on the surface, and this may be associated

with a potential pathogenicity of the dust.

Surface areas

Contact between silica particles and the cell membrane

can be regarded as the first step in macrophage

activation. Any adsorption of endogenous matter can

influence the pathogenic response to a silica

particle. In this respect, surface area is important

in the pathogenicity of a silica dust (29, 32).

Silicas have a wide range of surface areas, from 0.1

(coarsely ground crystalline or vitreous silica) to

1000 m2/g (precipitated and porous amorphous silica).

Commercial silicas are generally made with a high

surface area to enhance their adsorptive properties.

Surface hydrophilicity

The various silicas can differ widely in their

hydrophilic behavior an account of the presence of

different amounts of hydrophilic and hydrophobic

patches. Hydrophilicity is mainly due to silanol

groups (Si-OH), while siloxane bridges (Si-O-Si)

impart hydrophobicity (33-35). The hydrophilic

character of the surface, in turn, greatly influences

protein adsorption and denaturation, and cell adhesion

(29, 36). Hemolytic activity is directly related to

the hydrophilicity of the surface (37) as is the

cytotoxicity (38).

Surface contaminants

Silica dusts, particularly natural ones, have wide

levels of surface impurities (aluminium, iron,

titanium, lithium, sodium, potassium and calcium)

which influence the hydrophilic character of the

surface, the surface charges, and the ability to

release free radicals in solution.

Surface defects

The covalent character of the Si-O bond means that,

during mechanical fracture, several reactive species

can be generated. These species then react with

atmospheric components, so that freshly fractured

surfaces are more reactive than aged ones. Some

radical functions in subsurface layers or microcracks

can survive a long time and still be present when the

particle reaches the biological environment. Surface

reactive species are likely to be involved in the

pathogenic effects of silica dusts (4, 39).

Adsorption of endogenous molecules

Silica adsorbs proteins, probably by hydrogen bonding

with silanols. One hypothesis for the action of silica

on some cell membranes was strong adsorption of the

external part of membrane proteins (40). Adsorption of

pulmonary surfactant can influence silica toxicity,

suppressing the in vitro cytotoxicity of quartz (41),

while in vivo it can be partially removed by enzymatic

digestion, restoring the original silica surface (40).

Free radical release

Crystalline silicas can release free radicals in

solution. Several particle-derived ROS have been

reported, such as hydroxyl radical, superoxide anion

and peroxides (42). The production of free radicals

involves surface radicals and iron impurities (43).

Free radical release is much higher on freshly ground

materials, where surface peroxide or hydroperoxides

are formed (30), so this step is more important in

freshly ground than aged silicas. Particle-derived

ROS, such as free radicals or peroxides, may be

implied in direct damage to the epithelial cells,

mediated by peroxidation of lipids, DNA and proteins.

These effects may enable mutations and proliferation

in epithelial cells to initiate neoplastic

transformation.

Reactions with endogenous molecules

Silica is characterized by a very low solubility which

is responsible for its high bio-persistence and long

term effects. Endogenous molecules, particularly

ascorbic acid, increase the solubility of crystalline

silica after adsorption onto the silica surface. This

implies a depletion of ascorbic acid from the lung

lining, which is one of the body's antioxidant

defenses and an increase in the release of

particle-derived ROS. Both effects increase the

pathogenic potential of quartz (44).

Silica-related pulmonary diseases

Chronic silicosis (nodular pulmonary fibrosis)

Chronic nodular pulmonary silicosis is a debilitating

disease afflicting people exposed for long periods to

the inhalation of dusts containing crystalline silica.

The disease usually develops 20 or more years after

exposure (45). It is a slowly progressive, focal

fibrotic disease affecting the lung parenchyma that

can cause death by insufficient gas exchange, heart

failure or infections. Chronic silicosis is the most

ancient occupational disease known.

Silicosis is caused by the inhalation of crystalline

silica dust, the amorphous form being mostly inert.

Properties required for prolonged reaction and chronic

silicosis mainly involve surface properties including

chemical function, as mentioned before.

Acute silicosis (alveolar proteinosis)

This usually occurs in occupations where silica is

fractured or ground into fine powders by mechanical

processes such as drilling, sandblasting, etc. Acute

silicosis becomes clinically apparent within only two

to five years after exposure and is a serious, often

fatal disease, resulting from acute injury to alveolar

lining cells with accumulation of surfactants, cell

debris, and proteinaceous material in the alveolar

spaces. Silicosis has been reported in young people

with relatively short exposure (48 months) (46).

Lung cancer (bronchogenic carcinoma)

Bronchogenic carcinoma, associated with the inhalation

of asbestos, acts synergistically with smoking habits.

This often confounds epidemiological evidence. It also

occurs in some experimental animals exposed to silica

dusts and is suspected to arise preferentially in

patients with silicosis (22).

Silica and the immune system

There are many reasons for investigating the effects

of silica on the immune system. Silica particles are

engulfed by immunocompetent cells and may trigger

different pathways of activation. The reaction may be

catalytic itself or may stem from a surface site that

is renovated at each macrophage ingestion. Only under

these conditions can a pathogenic mechanism acting

such a long time after exposure be explained, or else

there may be a chemical basis for an immune response:

what happens after inflammation caused by urate

crystals might be an example.

Silica plays an experimental role of adjuvant (in 47)

and can induce immune dysfunctions such as a decrease

in OKT8+ cells (48), depression of the phagocytic

capacities of the reticuloendothelial system in

clearing circulating ICX (49) and increasing

polyclonal antibody synthesis, especially of IgA and

IgG (50).

Proteins (fibrinogen, IgG, albumin), phospholipids and

metal ions adsorbed onto the surface of quartz are

denatured and may acquire antigenic properties. Thus,

free silica particles may modify the structures of

some renal proteins and produce antigen. This is old

knowledge, as it was reported a long time ago that

plasma protein adsorbed on silica dust acquired

antigenic properties (51).

Last, other silica-related effects may be relevant in

autoimmunity: free radical-induced damage to DNA

(mainly in the presence of iron), eventually leading

to modification of the genome, lipid peroxidation,

cytotoxicity to macrophages and macrophage-like cells,

membranolysis.

From a laboratory point of view, up to 44% of patients

with silicosis have positive antinuclear factor and

ANCA (52-55). From a clinical point of view, an

increased prevalence of scleroderma has long been

reported and in fact this association eventually led

to compensation for progressive systemic sclerosis as

an occupationally-related disorder in miners (56-58).

Associations with a variety of other autoimmune

diseases have been reported, including rheumatoid

arthritis, SLE, connectivitis, Goodpasture syndrome,

Wegener and other vasculitis (59-67 ).

Silica and tuberculosis

The " highly fatal consumptive disease of the lungs in

hard-rock miners " described by G. Agricola in the 16th

century was considered the result of tuberculosis

(TBC) and silicosis.

Many occasional reports documented an association

between silicosis and TBC (45, 61, 69-71). Despite the

dramatic reduction in the prevalence of TBC in the

20th century, the annual incidence of TBC is three

times higher in men with silicosis (2707/100,000) than

men without silicosis (981/100,000 in South Africa)

(71). Furthermore, 42% of workers with silicosis (i.e.

25% of 5406 hematite miners in China) had TBC (70).

Mycobacterium tuberculosis is a significant human

pathogen capable of replicating in mononuclear

phagocytic cells. Immunity to Mycobacterium

tuberculosis infection is associated with the

emergence of protective CD4 T cells that secrete

cytokines, resulting in activation of macrophages and

the recruitment of monocytes to initiate granuloma

formation (72). An extensive review of the

relationship between TBC and autoimmune vasculitis is

beyond the scope of this paper. However, a subtle,

fascinating link connects silica, TBC and autoimmune

vasculitis, perhaps through some particularity in

macrophage function, as reported for the association

between a variation of the gene for

natural-resistance-associated macrophage protein I

(NRAMPI) and susceptibility to TBC in West Africans

(73).

Epidemiologic survey of the relationship between

silica and renal diseases

From an epidemiological point of view, relationships

between silica and renal disease have two main facets:

a) studies published by epidemiology units, or

institutes for occupational safety and health, dealing

with signs of renal diseases and deaths due to renal

diseases in workers (silica exposure * renal disease)

studies published by nephrology units or dialysis

registers, evaluating the frequency and type of

professional exposure among patients (renal disease *

silica exposure).

As in any setting of occupational diseases,

associations have often been identified from case

reports, then in clusters, and ultimately in

experimental models in animals and epidemiological

studies in populations.

Silica exposure * renal disease

As regards renal diseases in subjects exposed to

silica, many case reports have drawn attention to the

possible nephrotoxic effects of silica (Tab. V).

Pioneer observations pointed to functional changes or

pathological alterations in autopsy studies of

patients who had died of overt silicosis: proteinuria,

concentrating defects or azotemia, focal thickening of

the basement membrane, focal proliferation of

endothelial and mesangial cells and proximal tubular

damage with droplet-like dystrophy. At that time, the

main pathogenetic hypotheses were based on a direct

toxic effect of silicon, and silicon content in renal

tissue was higher than normal (74-76, 78).

These works use the term " silicon nephropathy " to

indicate pathological and functional changes thought

to be due to excessive renal accumulation of silicon,

affecting predominantly the glomerulus and the

proximal tubules: mild mesangial proliferation,

mesangial interposition, epithelial foot process

fusion, periglomerular fibrosis, epithelial

cytoplasmic vacuolization and granularity with densely

osmiophilic material in cytosomes. Immunofluorescent

findings were negative.

Pathological findings in the kidney were similar to

the abnormalities seen with nephrotoxic heavy metals

and the proximal tubular changes resembled certain

features seen in patients with Fanconi syndrome. In

other cases, however, silicosis was absent and renal

damage appeared in a context of autoimmune disease,

such as systemic vasculitis or Wegener's syndrome (24,

47, 77-82).

Bolton still used the term silicon nephropathy, but

did not measure the silicon concentration in kidney

tissues, and first suggested an immunological

hypothesis on the basis of serological abnormalities

(antinuclear antibodies) and the clinical course,

since renal damage responded to intravenous

methylprednisolone steroid pulses (47). Similar

favourable results with steroids, plasma-exchange and

immunosuppressants were reported by others (24, 28,

79). Osorio, who again showed silicon-composed

birifrangent crystals within the tubules, first called

attention to the absence of pulmonary involvement

(78).

It is remarkable that mines are not the most frequent

exposure, and a case has even been described in which

exposure was not related to any occupational hazard.

As mentioned earlier, a young woman who had inhaled

Ajax cleanser daily when she was ten years old, showed

diffuse pulmonary nodular densities when she was 21

years old, developed collagen vascular disease with

mild renal involvement when she was 35 years old, and

died six months later because of pulmonary

insufficiency (8).

In the absence of systematic epidemiologic studies or

a pathognomonic signature specific to silica-induced

nephropathy, it is certainly possible that the renal

disease in these few silica-exposed workers may be

coincidental. A chance association becomes less

plausible as more cases are reported and ­ more

important ­ as epidemiological studies designed to

test these hypotheses confirm the association.

Some population-based epidemiological evidence, often

obtained by retrospective analysis of cohorts in

occupational groups exposed to silica as well as other

potential hazards, suggested or denied that mortality

from renal disease was increased in silica-exposed

workers (83-97, Tab. VI). In the United Kingdom, a

statistically significant 62% excess of deaths from

genitourinary disease in miners and quarrymen has been

reported, and in the USA excess deaths from chronic

renal failure (CRF: chronic and unspecified nephritis

and renal sclerosis, 7 observed versus 2 expected)

were observed in retrospective cohort mortality

studies limited to the crude information about renal

disease from death certificates (in 78) and among

workers producing manufactured mineral fibers from the

USA multiplant cohort mortality study (91); occupation

likely to experience silica exposure is associated

with elevated standardized mortality ratio (SMR) for

deaths due to nonmalignant disease of urinary organs,

with a higher SMR for diseases of urinary organs

compared with US expected mortality (farmers 1.65,

farm-workers 1.31, brick and stone masons 2.30, other

construction workers 1.75, operating engineers 2.59)

(98). No such excess has been found in Finnish and

American quarrymen (87, 90) or Italian miners (94, 95)

..

In 1993, in a review of published data (91, 99, 100)

Goldsmith concluded that " if any of the three data

sets alone would be considered interesting but not

very convincing evidence of a silica-related excess of

renal diseases, taken together they are more

convincing " (18).

A high blood concentration of silicon is found in

persons with renal failure (110 mg/L in healthy

subjects, 1140mg/L in patients with CRF, 5000mg/L

after hemodialysis) but it has been interpreted as

evidence that the buildup of silica is due to renal

failure rather than vice-versa, also because of

silicon- contaminated dialysis fluids (101). As

mentioned before, the authors add that Balkan

nephropathy has been associated with consumption of

water rich in silica and that in the Negev of Israel,

the Bedouins, thought to be a population with maximal

exposure to dust storms (a vehicle for increasing

respiratory uptake of silica) have higher rates of

ESRF than Jews in the age group over 60 years. The

authors concluded that the evidence is consistent with

­ but not yet compelling ­ exposure to silica

increasing the long-term risk of renal disease

including renal failure.

As limitations might arise from the fact that these

data were obtained from retrospective analysis and

crude death certificates, more useful insights could

be expected from studies dealing with renal

involvement. The level of detail usually present on a

death certificate may not be sufficient , because

renal diseases are coded in broad nonspecific

categories. Therefore, the investigations examining

the occurrence of end stage renal failure (ESRF)

needing chronic dialysis provide investigators with a

new powerful tool for examining the risk of renal

damage.

Two epidemiological studies examined ESRF needing

chronic dialysis in occupational cohorts (13, 97).

The first reports the ESRF incidence in a large

occupational cohort (2412 white male gold miners in

South Dakota) in comparison with the incidence rates

of treated ESRD in the US population, providing

evidence that silica exposure is associated with an

increased risk for ESRF [standardized incidence ratio

(SIR) 1.37, 95% CI 0.68-2.46], especially ESRD caused

by GN or interstitial nephritis (SIR 4.22, 95%CI

1.54-9.19) increasing to 7.70, 95%CI 1.59-22.48 among

workers with ten or more years of employment

underground (13).

An Italian study found that silica-exposed ceramic

workers experience an excess of ESRF, by analyzing the

registry of patients on chronic dialysis in the Lazio

Region: observed/expected (O/E) was 3.21, 95% CI

1.17-6.98, non smokers O/E 4.34, smokers O/E 2.83,

nonsilicotic O/E 2.78, silicotic O/E 11.1, subjects

with <20 years since first employment O/E 5.5.

Therefore, occupational silica exposure is associated

with an increased risk for ESRF, the risk being

greatest for non systemic ESRF, especially if caused

by GN, and with an average silica exposure of eight

years (97).

Let us look at two expected objections:

1) We are still dealing with data that identify

individuals with renal disease once they have reached

end stage, that is functional death of the kidneys,

eventually needing continuous replacement therapy. The

exact nature of the pathogenic link between silica and

renal disease might be elucidated using a more

moderate end-point, such as the development of early

symptoms or the beginning of renal failure;

2) We are still dealing with data related to subjects

exposed to an occupational hazard 10-20 years ago. Is

this exposure-related risk still operating, both in

terms of the number of people exposed and the

intensity of exposure?

To answer these important questions, we can look at

other studies, for instance those that look for early

signs of renal dysfunction in subjects exposed to

silica. Studies of whether short exposure to silica

induced signs of renal dysfunction (low molecular

weight proteinuria and enzymuria) before there was any

sign of pulmonary involvement found increased

excretion of albumin, retinal-binding protein and

N-acetyl-beta-D-glucosaminidase in exposed subjects

(92). Further confirmation of this subclinical effect

on kidney function in young workers with short

exposure to silica (11-20 months) and without any sign

of silicosis has been reported by other authors (96).

As to the second question, estimates of the total

number of subjects exposed (only speaking of the

mining, stone-cutting, and abrasive industries) still

deal with 1.2 to 3 million people (102). Furthermore,

the mortality study of workers hired before 1930

focused on cumulative silica exposure exceeding 1.31

mg/m3. In contrast, current studies can detect an

increased risk of renal diseases among miners with

more recent and lower silica exposure with highest

cumulative silica dust exposure 0.77 mg/m3-years (13).

TABLE V - CASE SERIES OF PATIENTS WITH COINCIDENCE OF

RENAL DISEASE AND SILICA EXPOSURE

TABLE VI - CLINICAL STUDIES ON RENAL INVOLVEMENT IN

WORKERS EXPOSED TO SILICA

* reference number in brackets

Abbreviations: ARF= acute renal failure, CRF= chronic

renal failure, RPGN= rapidly progressive

glomerulonephritis,

GN= glomerulonephritis, RDT= Regular dialytic

treatment, SMR= standardised mortality ratio, OR=odds

ratios

Renal disease * silica exposure

If silica exposure leads to nephritis or other renal

damage, persons with such exposure should be found in

excess among patients being treated for ESRF (Tab.

VII). Among 73 cases of rapidly progressive GN (RPGN)

observed from 1977 to 1988, Dracon reported 11 (15 % )

subjects working as miners: 8 with negative

immunofluorescent findings, and 3 with IgA and IgG

deposits (25). Three patients had renal arteriolitis,

two hemoptysis and pulmonary silicosis. Considering

their data from another point of view, the authors

wrote that, among 43 biopsies from patients with

silicosis, 65% showed GN of any type and 26% rapidly

progressive, whilst the prevalence of this latter type

was only 6.8% among all patients who underwent renal

biopsy in their French renal unit.

In the same year, Steenland published a case-control

study in American patients: 325 men with ESRF and 325

male controls matched for age, race and area of

residence were interviewed by telephone. Eighty-seven

(27%) patients and 54 (17%) controls had been exposed

to silica, with odds ratios of 1.92 for brick and

foundry workers and 3.83 for sandblaster (100).

In the first Italian study, by Gregorini, 7/16

patients (44%) with ANCA- associated RPGN had been

exposed to silica as compared with 1/32 controls

(age-matched subjects admitted for other renal disease

in the same historical period) (103, 104).

In a small European case-control study, Nuyts reported

that 44% of patients with Wegener's granulomatosis had

exposure to silicon compounds, but not to other

occupational risk factors (105), and in a larger

occupational history of 272 patients with CRF, (19%)

exposure to silicon containing compounds such as sand,

cement, coal, rocks and grain dust was significantly

higher than in 272 controls matched for age, sex and

region of residence (106). Significant occupational

risk factors for CRF were found for exposure to lead

(OR 2.11), copper (OR 2.54), chromium (OR 2.77), tin

(OR 3.72), mercury (OR 5.13), welding fumes (OR 2.06),

oxygenated hydrocarbons (OR 5.45), silicon containing

compounds (OR 2.51), or grain dust (OR 2.96).

Lastly, in a case- control study in Italian patients

followed at a single center, Stratta compared the

occupational histories of 31 patients with

biopsy-proven vasculitis (18 paucimmune crescentic GN,

9 microscopic polyangioitis, 4 Wegener's

granulomatosis) with those of 58 age, sex and

residence-matched controls (with other kidney

diseases). Occupational health physicians designed a

special questionnaire to evaluate and calculate a wide

spread of exposures using the product of intensity x

frequency x duration. A history of exposure to silica

was significantly more frequent among cases (14/31,

45%) than controls (14/58, 24%, p=0.04, OR 2.4) and no

other significant exposure association was found,

including asbestos, mineral oil, formaldehyde, diesel

and welding fumes, grain and wood dust, leather,

solvents, fungicides, bitumen, lead, paint. Past TBC

infection was also significantly frequent among

patients with vasculitis (12/45, 26%) than controls

(4/45, 8%, p<0.05) (107).

A very similar study by the Glomerular Disease

Collaborative Network in USA, obtained similar results

in 61 patients, confirming that the association with

silica exposure is typical of ANCA­pos small vessel

vasculitis and is not shared by other autoimmune

diseases such as SLE nephritis (108).

Worth noting is the fact that, according to EDTA data,

less than 5% of new dialysis patients each year have

nephropathy induced by a toxic agent (109), whilst the

Occupational Center for Disease argued that up to 50%

of cases of ESRF may be induced by toxic agents since

they are diagnosed as CRF of unknown etiology, GN and

unspecified interstitial nephritis (110). The

prevalence of toxin-induced renal failure may thus be

underestimated.

TABLE VII - CLINICAL STUDIES ON SILICA EXPOSURE IN

PATIENTS WITH RENAL DISEASE

* reference number in brackets

Reasons for a link between silica and renal diseases

The suspicion that silica dust affects the kidney is

at least 50 years old.

Now, however, we have to answer the question whether

relationships between silica exposure and human

diseases must be considered only in terms of the

quantitative dose/effect ratio (dealing with toxic

effects) or in a qualitative fashion, depending on

cellular effects and pathogenic mechanisms different

from those simply explained by toxicity, and including

autoimmune pathways. Available data support both these

approaches.

Silica as nephrotoxin

In studies up to 1975, 51% of patients who died of

advanced silicosis showed extensive renal damage. This

damage was mainly thought to be related to the toxic

effect of the silicon load: 200-250 ppm (mg/Kg dry

weight) in patients with renal failure, in contrast to

normal values of 13-14 or 23-25 ppm (mg/Kg dry weight)

(74-76). Silica was considered responsible for damage

in endothelial and epithelial cells, as documented by

foot process obliteration, altered lysosomes, dense

particles in cytosomes, eventually leading to

disruption of the polyanion sialoprotein coat which

repels polyanionic serum proteins and prevents their

passage into the urinary space. The absence of

proximal tubular dysfunction, despite significant

ultrastructural changes, was explained by the lack of

effect of silica on the NA-K-ATPase system, in

contrast to metals such as cadmium.

Local accumulation of silica suggests direct tissue

toxicity, as silicon is partly eliminated by the

kidney and excessive amounts tended to accumulate in

the kidneys of patients exposed to inhalation. Silica

particles are nephrotoxic in experimental settings,

and the ultrastructural changes in silica-related

renal damage are similar to those seen in animals

given puromycin aminonucleosides which are cytotoxic.

Experimental work showed that silica has a direct,

dose-dependent toxic effect on the kidney. Although it

is difficult to summarize the experimental studies

conducted in different species with various silica

compounds and modes of administration, they do all

conclude that silica is nephrotoxic and this toxicity

is apparently dose-related (111, 112)

Silica as a trigger of immune reaction

In recent years, rapidly progressive renal failure has

been reported in patients with acute silicosis. There

are also cases of renal disease in the absence of

clinical silicosis, suggesting that for certain

silica-exposed individuals renal damage may be the

initial and dominant adverse effect.

Bolton first focused on a distinct autoimmune aspect

in those patients, where there was an immunologic

event with a lupus-like presentation (arthralgia,

arthritis, and other musculoskeletal symptoms

associated with serological abnormalities seen with

active SLE, including an elevated erythrocyte

sedimentation rate, positive antinuclear factor and LE

preparation), suggesting that silicotic lesions may

arise from interaction of macrophage with silicon, and

improvement was seen after pulse methylprednisolone

therapy (47).

In patients with immunological abnormalities it is not

clear whether these are directly responsible for renal

injury or are a response to the direct toxic effect of

silica. Renal damage may be the result of a

maladaptive immunological response evoked by the

destructured components of granulomatous pulmonary

nodules containing silica-based materials; or, damage

to lung cells may induce antibody production,

cross-reacting with renal antigens. Another

possibility is that protein absorbed onto the surface

of silica (in the pulmonary or renal vascular bed) may

be denatured and might possibly acquire antigenic

properties. Thus, free silica particles may modify the

structures of some pulmonary/renal proteins and

produce antigen.

Silica and renal clinical/pathological findings

There is no single pathognomonic clinical or

laboratory finding of silica-induced GN. In chronic

forms, subclinical alterations suggest that initial

renal tubular dysfunction is followed by glomerular

injury. This information may be useful to select

markers of renal injury for screening silica exposed

workers.

However, rapidly progressive renal failure has been

reported, as well as clinical pictures of systemic

autoimmune diseases.

Histological findings of a focal or diffuse

proliferative GN with ultrastructural features of

subendothelial deposits and increased tubular

" cytosegresomes " (with a high silica concentration in

renal tissue) are strong circumstantial evidence, but

pauci-immune necrotizing crescentic GN with either

completely negative immunofluorescence findings or

nonspecific granular IgM or C3 deposits along the

capillary wall have been described or, in some cases ,

mesangial IgA and C3 deposits compatible with IgA

nephropathy.

How silica reaches the kidneys

Inhalation can result in a variety of lesions due to

lymphohematogenous spread to the liver, spleen,

kidney, bone marrow and extrathoracic lymph nodes, but

many other ways for silica to enter the human body are

amply documented, and different types of silica may be

related to different types of damage.

Conclusions

By writing this review, we hope to alert nephrologists

to the potential relationship between silica exposure

and renal diseases. We would like to conclude by

issuing a challenge, first, to ourselves:

How many times last year did we look throughly for

occupational exposure in patients reaching ESRF of

unknown etiology or because of so-called

" nephroangiosclerosis " ?

How many times last year did we look throughly for

occupational exposure in patients reaching ESRF of

biopsy-proven (or clinical-based) known etiology, in

order to assess a possible accelerating role for

environmental nephrotoxins?

There are several reasons why it is difficult to

identify nephrotoxins: the long latency between

exposure and onset of CRF and ESRF (the mean latency

in the Calvert cohort was 36 years) (13), the

nonspecific appearance of renal disease once it has

become symptomatic, and the fact that ESRF in a

toxin-exposed individual is often influenced by a

complex interaction involving other toxins,

nutritional and environment factors and genetic

susceptibility. Then too, the historically poor

training of physicians in occupational medicine

persists, as does the subtle or occasionally not so

subtle-influence of corporations on academic research

and government regulations.

There is ­ to conclude ­ no single specific clinical

or laboratory finding of silica-induced nephropathy:

we know, by now, that renal involvement may follow a

toxic effect or arise in a context of autoimmune

disease, and that silica-induced renal damage may

operate as an additive factor on an existing

established renal disease, as in diabetes, primary or

secondary GN. In fact, nephrotoxic substances not only

causes renal diseases directly, but they can also

destroy renal reserve, potentially placing people with

additional risk factors, such as GN, diabetes,

hypertension, cardiovascular disease and genetic

predisposition, at greater risk.

An occupational history should be obtained for all

patients, with particular attention to silica, heavy

metals, and solvent exposure among renal patients. A

thorough occupational history is critical not only in

evaluating patients with otherwise unexplained renal

insufficiency, but also patients with recognizable

causes of renal disease. Excluding renal diagnoses

thought to be related to non-occupational causes

(diabetes nephropathy, polycystic disease, SLE

nephropathy and unspecified CRF) may be misleading.

Exposure may have contributed to the development of

CRF in virtually all diagnostic groups.

We also wish to alert the occupational health

community to the fact that renal damage may precede

pulmonary involvement in silica-exposed workers.

Further epidemiological studies are needed to document

the rates of glomerular diseases in silica-exposed

populations with and without silicosis. Such studies

should assess whether the current occupational

standard for silica adequately protects workers from

renal diseases.

For diseases occurring years after initial exposure,

there is a tendency to ascribe the current disease

incidence to historical workplace conditions. However,

modern technologies used in the absence of modern

controls continue to pose a health risk and allow

these diseases to persist (17).

Let us summarize the answers to the main foreseeable

questions:

- silica nephrotoxicity without silicosis?

Yes, because the occurrence of renal diseases in the

absence of pulmonary diseases is by now firmly

demonstrated. Evidence suggest that renal disease may

be the dominant adverse effect among some

silica-exposed individuals

- silica nephrotoxicity outside mines?

Yes, quartz being the primary source of silica and

quartz being almost ubiquitous on the earth's crust.

This implies that workers are exposed to silica in

occupations and industries other than mines

(quarrying, tunneling, foundry work, glass

manufacture, abrasive blasting, ceramic and pottery

production, cement production, jewellery, etc.). Even

the general population can be exposed to the silica

hazard, in particular conditions such as those

reported for Bedouins or for people suffering from

Balkan nephropathy (18). Biogenic amorphous silicas

which are easily converted into finely divided

partially crystalline dusts may also be of some

concern.

- silica nephrotoxicity despite today's protective

measures for workers?

Yes, because the median intensity of exposure to

silica dust was 0.04 mg/m3 in studies demonstrating

significantly higher odds ratios for ESRF in exposed

people (13). Thus, the current Occupational Safety and

Health Agency (OSHA) standard of 0.09 mg/m3 may not

ensure adequate protection against the nephrotoxic

effect. Furthermore, although silica exposure was

reduced after 1950, the risk for nonsystemic ESRF

remained elevated even when only workers first

employed underground after 1950 were included in the

analysis ( SIR 5.00, 95% CI 1.03-14.61); the median

intensity of silica exposure among this subgroup of

workers was only 0.02 mg/m3 (13).

Note that a study in New Jersey in 1989 demonstrated

that 60 individuals affected per year in a state is a

number that escapes detection (extrapolation of their

data predicted 1500 individuals as having silicosis as

against 2590 diagnosed from nationwide reports). Data

from the national system are therefore understimates.

Their data did not support the view that silicosis is

only a disease of historical interest and some concern

remains about current working conditions, as medical

surveillance was found to be adequate in only 25% of

companies investigated (113).

Warnings:

The evidence for the nephrotoxicity of silica

continues to mount (13).

Silica toxicity still occurs, not only in mines, and

even beyond occupational exposure.

Silica toxicity may develop in the absence of

silicosis.

Silica toxicity may cooperate in progression of renal

damage due to any cause.

In contrast to overt pulmonary silicosis which

progresses even if exposure ceases, some reports

suggest that withdrawal of exposure may stop or allow

toxicity to be cured.

Silica should be regarded as only the tip of an

iceberg of environmental and occupational risk for

renal damage (114-118).

" Physicians can contribute to disease prevention

through accurate diagnosis and reporting of these

conditions and through effective health communication "

(17).

Reprint requests to: Prof. Piero Stratta - Department

of Internal Medicine, Nephrology Section S.Giovanni

Molinette Hospital Corso Bramante, 88 10126 Torino,

Italy strattanefro@...

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Received: December 18, 2000 Revised: May 15, 2001

Accepted: June 21, 2001